N-[piperazinyl hetaryl]arylsufonamide compounds with affinity for the dopamine D3 receptor

ABSTRACT

The invention related to N-[(piperazinyl)hetaryl]arylsulfonamide compounds of the general formula (I) in which Q is a bivalent, 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents R a  which is/are selected, independently of each other, from halogen, CN, NO 2 , CO 2 R 4 , COR 5 , C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; Ar is phenyl or a 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents R b , which is/are selected from halogen, NO 2 , CN, CO 2 R 4 , COR 5 , C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, with it also being possible for two radicals R b  which are bonded to adjacent C atoms of Ar to be together C 3 -C 4 -alkylene; R 1  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl or C 3 -C 4 -alkynyl; with the radicals n, R 1 , R 2 , R 3 , R 4  and R 5  having the meanings given in the patent claims, to the N-oxides and to the physiologically tolerated acid addition salts of these compounds and to pharmaceutical compositions which comprise at least one N-[(piperazinyl)hetaryl]arylsulfonamide compound as claimed in one of claims  1  to  10  and/or at least one physiologically tolerated acid addition salt of I and/or an N-oxide of I, where appropriate together with physiologically acceptable carriers and/or auxiliary substances for treating diseases which respond to influencing by dopamine D 3  receptor antagonists or agonists, in particular for treating diseases of the central nervous system and disturbances of kidney function.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 10/552,842, filed on Aug. 22, 2006, which is the U.S. National stage entry of International Patent Application No. PCT/EP2004/003872, filed on Apr. 13, 2004, which claims priority to U.S. patent application Ser. No. 10/413,233, filed on Apr. 14, 2003, the contents of all of which are hereby incorporated by reference.

The present invention relates to novel N-[(piperazinyl)hetaryl]arylsulfonamide compounds. The compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases which respond to modulation of the dopamine D₃ receptor.

Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large number of substances exert their effect by way of these receptors. One of them is dopamine. Confirmed findings exist with regard to the presence of dopamine and its physiological function as a neurotransmitter. Disturbances in the dopaminergic transmitter system result in diseases of the central nervous system which include, for example, schizophrenia, depression and Parkinson's disease. These diseases, and others, are treated with drugs which interact with the dopamine receptors.

Up until 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D₁ and D₂ receptors. More recently, a third subtype was found, namely the D₃ receptor which appears to mediate some effects of antipsychotics and antiparkinsonians (J. C. Schwartz et al., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514, J. N. Joyce, Pharmacology and Therapeutics 2001, 90, pp. 231-59 “The Dopamine D₃ Receptor as a Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs”).

Since then, the dopamine receptors have been divided into two families. On the one hand, there is the D₂ group, consisting of D₂, D₃ and D₄ receptors, and, on the other hand, the D₁ group, consisting of D₁ and D₅ receptors. Whereas D₁ and D₂ receptors are widely distributed, D₃ receptors appear to be expressed regioselectively. Thus, these receptors are preferentially to be found in the limbic system and the projection regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions, such as the amygdala. Because of this comparatively regioselective expression, D₃ receptors are regarded as being a target having few side-effects and it is assumed that while a selective D₃ ligand would have the properties of known antipsychotics, it would not have their dopamine D₂ receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D₃ Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

Compounds having an affinity for the dopamine D₃ receptor have been described in the prior art on various occasions, e.g. in WO 96/02519, WO 96/02520, WO 96/02249, WO 96/02246 and DE 10131543 and WO 99/02503. Some of these compounds possess high affinities for the dopamine D₃ receptor. They have therefore been proposed as being suitable for treating diseases of the central nervous system. Some of the compounds described in these publications possess a piperazinylhetaryl structure.

The invention is based on the object of providing compounds which act as selective dopamine D₃ receptor ligands.

This object is achieved by means of N-[(piperazinyl)hetaryl]arylsulfonamide compounds of the general formula I

in which

-   R is oxygen, a group N—R³ or a group CR^(3a)R^(3b); -   Q is a bivalent, 6-membered heteroaromatic radical which possesses 1     or 2 N atoms as ring members and which optionally carries one or two     substituents R^(a) which is/are selected, independently of each     other, from halogen, CN, NO₂, CO₂R⁴, COR⁵, C₁-C₄-alkyl,     C₁-C₄-alkoxy, C₁-C₄-haloalkyl, NH₂, NHR⁶, NR⁶R⁷ and     C₁-C₄-haloalkoxy; -   Ar is phenyl or a 6-membered heteroaromatic radical which possesses     1 or 2 N atoms as ring members and which optionally carries one or     two substituents R^(b), which is/are selected from halogen, NO₂, CN,     CO₂R⁴, COR⁵, NH₂, NHR⁶, NR⁶R⁷, C₁-C₆-alkyl, C₁-C₆-haloalkyl,     C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl,     C₃-C₆-cycloalkyl, C₃-C₆-cycloalkoxy, C₃-C₆-cycloalkyl-C₁-C₄-alkyl     and C₁-C₄-haloalkyl, with it also being possible for two radicals     R^(1b) which are bonded to adjacent C atoms of Ar to be together     C₃-C₄-alkylene; -   n is 0, 1 or 2; -   R¹ is hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,     C₃-C₆-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl,     C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₄-alkenyl or C₃-C₄-alkynyl; -   R² is C₁-C₄-alkyl, C₁-C₄-haloalkyl or, together with R¹, is     C₂-C₅-alkylene or, in the case of n=2, the two radicals R² can     together be C₁-C₄-alkylene; -   R³ is hydrogen or C₁-C₄-alkyl; -   R^(3a), R^(3b) are, independently of each other, hydrogen or     C₁-C₄-alkyl; -   R⁴ is C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₂-C₄-alkenyl C₃-C₆-cycloalkyl,     C₃-C₆-cycloalkyl-C₁-C₄-alkyl, phenyl or benzyl; -   R⁵ is hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₂-C₄-alkenyl     C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₄alkyl, phenyl or benzyl; and -   R⁶, R⁷ are each independently selected from C₁-C₄-alkyl,     C₁-C₄-haloalkyl or together with the nitrogen to which they are     bound form a saturated 3-, 4-, 5- or 6-membered heterocycle, which     additionally may comprise an oxygen atom or an additional nitrogen     atom as a ring member and which may carry 1, 2, 3 or 4 C₁-C₄ alkyl     groups;     the N-oxides thereof and the physiologically tolerated acid addition     salts of these compounds.

These compounds have not previously been described, with the exception of 4-methyl-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzenesulfonamide and 4-chloro-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzenesulfonamide, which are offered for sale by Ambinter, Paris, as test substances for exploratory libraries.

The present invention therefore relates to N-piperazinyl)hetaryl]arylsulfonamide compounds of the general formula I, to their N-oxides and to their physiologically tolerated acid addition salts, with the exception of the compounds 4-methyl-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzenesulfonamide and 4-chloro-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzenesulfonamide.

The present invention also relates to the use of N-[(piperazinyl)hetaryl]arylsulfonamide compounds of the general formula I, of their N-oxides and of their acid addition salts for producing a pharmaceutical composition for treating diseases which respond to the influence of dopamine-D₃ receptor antagonists or agonists.

The diseases which respond to the influence of dopamine D₃ receptor antagonists or agonists include, in particular, disturbances and diseases of the central nervous system, in particular affective disturbances, neurotic disturbances, stress disturbances and somatoform disturbances and psychoses, especially schizophrenia and depression and, in addition, disturbances of kidney function, in particular kidney function disturbances which are caused by diabetes mellitus (see WO 00/67847).

According to the invention, at least one compound of the general formula I having the meanings mentioned at the outset is used for treating the abovementioned indications. Provided the compounds of the formula I possess one or more centers of asymmetry, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers, diastereomers and tautomers.

It is likewise possible to use physiologically tolerated salts of the compounds of the formula I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C₁-C₄alkylsulfonic acids, such as methanesulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhä user Verlag, Basel and Stuttgart, 1966.

It is likewise possible to use N-oxides of the compounds of the formula I. In the N-oxides of the compounds of the formula I, one or more of the N atoms which is/are ring members, and in particular ring members in the aromatic heterocycles Q and/or Ar, are present as an N-oxide group. Preference is given to those N-oxides of the formula I in which the ring nitrogen atoms in the piperazine ring do not form any N-oxide group. Particularly preferred N-oxides exhibit a N-oxide group on one or two of the ring nitrogen atoms of Ar and/or Q.

Here and in that which follows, halogen is fluorine, chlorine, bromine or iodine.

C_(n)-C_(m)-Alkyl (in radicals such as alkoxy, alkoxyalkyl, alkylthio, alkylamino, dialkylamino etc., as well) is a straight-chain or branched alkyl group having from n to m carbon atoms, e.g. from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl and the like.

C₁-C₄-Haloalkyl (in radicals such as haloalkoxy, haloalkoxyalkyl, haloalkylthio, etc., as well) is an alkyl group having from 1 to 4 C atoms in which all or some, e.g. 1, 2, 3 or 4 of the hydrogen atoms, is/are replaced by halogen atoms, in particular by chlorine or fluorine. Preferred haloalkyl is C₁-C₂-fluoroalkyl or C₁-C₂-fluorochloroalkyl, in particular CF₃, CHF₂, CF₂Cl, CH₂F, and CH₂CF₃.

C₁-C₄-Hydroxyalkyl is a C₁-C₄-alkyl group which possesses an OH group, such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 2-methyl-2-hydroxypropyl etc.

C₁-C₄-Alkoxy-C₁-C₄-alkyl is a C₁-C₄-alkyl group which carries a C₁-C₄-alkoxy substituent, e.g. methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, (1-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH₂—OC(CH₃)₃, 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl, 2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n-propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl, 2-(1,1-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3-(n-butoxy)propyl, 3-(1-methylpropoxy)propyl, 3-(2-methyl-propoxy)propyl, 3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl, 2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl, 2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl, 2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl, 3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl, 3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl, 3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl, 4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl, 4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl or 4-(1,1-dimethylethoxy)butyl, preferably methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl or 3-(methoxy)propyl, or 3-(ethoxy)propyl.

C₃-C₆-Cycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

C₃-C₆-Cycloalkyl-C₁-C₄-alkyl is a C₁-C₄-alkyl group which carries a C₃-C₆-cycloalkyl radical, e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 1-cyclopropylpropyl, 1-cyclobutylpropyl, 1-cyclopentylpropyl, 2-cyclopropylpropyl, 2-cyclobutylpropyl, 2-cyclopentylpropyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 1-cyclopropyl-1-methylethyl, 1-cyclopentyl-1-methylethyl, 1-cyclopentyl-1-methylethyl, 3-cyclohexylpropyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexyl-1-methylethyl or 1-cyclohexyl-1-methylethyl. C₂-C₄-Alkenyl (in radicals such as alkenyloxy as well) is a singly unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 C-atoms, e.g. vinyl, allyl(2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and the like. C₃-C₄-Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.

C₃-C₆-Alkynyl (in radicals such as alkinyloxy as well) is a hydrocarbon radical having 2, 3, 4, 5 or 6 C atoms which possesses a triple bond, e.g. propargyl (2-propyn-1-yl), 1-methylprop-2-yn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 1-pentyn-3-yl, etc.

Examples of 6-membered heteroaromatic radicals which possess 1 or 2 nitrogen atoms as ring members are, in particular, 2-, 3- or 4-pyridinyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazinyl and 3- or 4-pyridazinyl. Examples of bivalent, 6-membered heteroaromatic radicals which possess 1 or 2 nitrogen atoms as ring members are, in particular, pyridin-2,4-diyl, pyridin-2,5-diyl, pyridin-2,6-diyl, pyridin-3,5-diyl, pyrimidin-2,4-diyl, pyrimidin-2,5-diyl, pyrimidin-4,6-diyl, pyrazin-2,5-diyl, pyrazin-2,6-diyl, pyridazin-3,6-diyl and pyridazin-3,5-diyl.

With regard to using the compounds according to the invention as dopamine D₃ receptor ligands, preference is given to those compounds of formula I in which the piperazin ring is bonded to the heteroaromatic radical Q in the meta position or, in particular, in the para position with respect to the group R.

In one embodiment the radical R^(a) is selected from halogen, CN, NO₂, CO₂R⁴, COR⁵, C₁-C₄-alkyl and C₁-C₄-haloalkyl. Preferred meanings of R⁴ and R⁵ are, independently of each other, H or C₁-C₄-alkyl. In another embodiment R^(a) is selected from C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, NH₂, NHR⁶ and NR⁶R⁷. In this embodiment preferred meanings of R⁶ and R⁷ are independently of each other methyl or ethyl.

The heteroaromatic radical Q may be unsubstituted or possess a substituent R^(a) which is selected from halogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl, C₁-C₄-alkoxy, NH₂, NHR⁶, NR⁶R⁷ and C₁-C₄-haloalkoxy. In one embodiment the radical R^(a) is selected from halogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl. In another preferred embodiment R^(a) is selected from C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, NH₂, NHR⁶ and NR⁶R⁷ with specific preference given to methoxy, NH₂, methylamino, dimethylamino, ethylamine, diethylamino and methylethylamino.

In a very preferred embodiment, Q is unsubstituted.

In another very preferred embodiment, Q carries a radical selected from C₁-C₄-haloalkoxy, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-alkyl, NH₂, NHR⁶ or NR⁶R⁷. and especially methoxy or methyl.

Preference is given to the variables Q, R¹, R², R³ and Ar preferably having, independently of each other, the meanings given below:

Q is preferably a radical of the formula A:

in which A₁, A₂ and A₃ are, independently of each other, N or CH, and one or two of the variables A₁, A₂ and A₃ can also be C—R^(a), with A₁, A₂ and A₃ not simultaneously being N or being simultaneously selected from CH and C—R^(a). In formula A, k is 0 or 1 and R^(a) has the previously mentioned meanings.

In formula A, R^(a) is preferably selected from halogen, especially chlorine or fluorine, C₁-C₄-alkyl, especially methyl, and C₁-C₄-haloalkyl, especially trifluoromethyl, C₁-C₄-alkoxy especially methoxy, C₁-C₄-haloalkoxy, especially difluormethoxy or trifluormethoxy, NH₂, NHR⁶ especially methylamino or ethylamino, and NR⁶R⁷, especially dimethylamino, diethylamino or methylethylamino. The C atom which is located between the atoms A₁ and A₃ preferably carries the piperazinyl radical.

In particular, none of the variables A₁, A₂ and A₃ is C—R^(a). Preferred radicals Q are those of formula A, in which A₁ and/or A₃ is/are N, the remaining variable A₁ or A₂ is CH or C—R^(a), A₂ is CH, and the piperazinyl radical is bonded to the C atom which is located between A₁ and A₃.

Preference is furthermore given to compounds of the formula I, in which A₁ and A₂ in formula A are N and A₃ is CH or C—R^(a).

In a very preferred embodiment k in formula A is 0. In particular, Q is pyridin-2,5-diyl or pyrimidin-2,5-diyl which are unsubstituted or able to possess a substituent R^(a) which is different from hydrogen. The piperazinyl radical is then preferably arranged in the 2 position.

In another very preferred embodiment k in formula A is 1, A₃ is N, A₁ and A₂ are, independently of each other, N or CH and R^(a) is selected from C₁-C₄-alkoxy, NH₂, NHR⁶, NR⁶R⁷ and C₁-C₄haloalkoxy. In particular R^(a) is methoxy or methyl. Most preferably the piperazine radical is located in the 2 position. In this embodiment compounds are especially preferred, in which A₁ is N or CH, in particular CH and A₂ is CH.

Ar is preferably phenyl or pyridyl which, where appropriate, possesses one or two of the abovementioned substituents R^(b). With regard to using the compounds according to the invention as dopamine D₃ receptor ligands, preference is given to those compounds of formula I in which Ar carries one substituent R^(b) in the para position and, where appropriate, a further substituent R^(b) in the ortho position or in the metaposition, in each case related to the binding site for the sulfonamide group. The radicals R^(b) may be identical or different. Preference is given to the radicals R^(b) in the para position being selected from C₂-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, NH₂, NHR⁶ and NR⁶R⁷.

In one preferred embodiment the radical R^(b) in the para position is selected from C₂-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, in particular, from branched C₃-C₆-alkyl, especially isopropyl, and C₃-C₆-cycloalkyl, especially cyclopropyl. Very particular preference is given to the radical R^(b) which is arranged in the para position of Ar being isopropyl.

In one preferred embodiment the radical R^(b) in the para position is selected from NHR⁶ and NR⁶R⁷. In this embodiment preferred meanings of R⁶ and R⁷ are independently of each other methyl or ethyl or form together with the N atom a saturated 3-, 4-, 5- or 6-membered heterocycle, which additionally may comprise an oxygen atom or an additional nitrogen atom as a Ting member and which may carry 1, 2, 3 or 4 C₁-C₄ alkyl groups, e.g. a radical from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl etc.

Preferred radicals R^(b) in the meta position or ortho position are selected from halogen, especially chlorine and fluorine, C₁-C₄-alkyl, especially methyl, CN, trifluoromethyl and difluoromethyl.

With regard to using the compounds according to the invention as dopamine D₃ receptor ligands, preference is given to those compounds of the formula I in which R¹ is different from hydrogen, in particular hydrogen and methyl. In particular, R¹ is C₂-C₃-alkyl, cyclopropylmethyl or, particularly preferably, ethyl, allyl or n-propyl.

The variable n is preferably 0 or 1. Provided n is ≠0, R² is preferably methyl. When n is ≠0, the group R² is preferably bonded to a carbon atom in the piperazine ring which is adjacent to the group R¹—N. In particularly preferred compounds, n=0. Particular preference is also given to compounds of the formula I in which it applies that n=1 and R² is a methyl group which is bonded to a carbon atom in the piperazine ring which is adjacent to the group R¹—N. The compounds can then be present as a racemate, as pure enantiomers or as nonracemic mixtures of the enantiomers. Among these, particular preference is given to those compounds in which the C atom which carries the methyl group exhibits the S configuration.

R³ is preferably hydrogen or C₁-C₄-alkyl and, in particular, hydrogen.

If R is a group CR^(3a)R^(3b), at least one of the radicals R^(3a) or R^(3b) is hydrogen. More preferably both radicals R^(3a) and R^(3b) are hydrogen.

Among the compounds of the general formula I, preference is given to the compounds I, wherein R is N—R³, wherein R³ is as defined above and especially H. Amongst these compounds preference is given to the compounds of the general formula Ia

in which n, R¹, R², R³, R^(a) and R^(b) have the previously mentioned meanings, in particular the meanings specified as being preferred, and in which A₁, A₂ and A₃ are, independently of each other, N or CH, and one of the variables A₁, A₂ and A₃ can also be C—R^(a), with A₁, A₂ and A₃ not simultaneously being N or simultaneously being selected from CH and C—R^(a), and X and Y are selected from CH, C—R^(b′) and N, in which R^(b′) is halogen, methyl, CN, difluoromethyl or trifluoromethyl, with X and Y not simultaneously being N or simultaneously being C—R^(b′), and k is 0 or 1. R^(a) has the previously mentioned meanings. In particular, R^(a) is selected from halogen, especially chlorine or fluorine, C₁-C₄-alkyl, especially methyl, and C₁-C₄-haloalkyl, especially trifluoromethyl, C₁-C₄-alkoxy especially methoxy, C₁-C₄-haloalkoxy, especially difluormethoxy or trifluormethoxy, NH₂, NHR⁶ especially methylamino or ethylamino, and NR⁶R⁷, especially dimethylamino, diethylamino or methylethylamino.

In particular, none of the variables A¹, A² and A³ is C—R^(a). Preferred compounds Ia are those in which A₁ and/or A₃ is/are N, the remaining variable A₁ or A₂ is CH or C—R^(a), A₂ is CH.

In particular preferred embodiment, k=0. Among these, preference is furthermore given to compound I in which A₁ and A₂ are N and A₃ is CH or C—R^(a). Among these, preference is given to those compounds of the formula Ia in which X or Y is CH or N and, in particular, both are CH.

In another very preferred embodiment k in formula Ia is 1, A₃ is N, A₁ and A₂ are, independently of each other, N or CH and R^(a) is selected from C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, NH₂, NHR⁶, NR⁶R⁷ and C₁-C₄-haloalkoxy. In particular R^(a) is methoxy or methyl. In this embodiment compounds are especially preferred, in which A₁ is N or CH, in particular CH and A₂ is CH.

Among the compounds of general formula Ia, preference is given to the compounds of general formula Ia.1

in which n, X, Y, R¹, R², R³, R^(a) and R^(b) have the previously mentioned meanings, in particular the meanings specified as being preferred, and q is 0, 1 or 2 and in particular 0 or 1. If q is 1, the radical R^(a) is preferably bound to the carbon atom which is adjacent to the nitrogen atom of the pyridine ring

Among the compounds of general formula Ia, preference is furthermore given to the compounds of general formula Ia.2

in which n, X, Y, R¹, R², R³, R^(a) and R^(b) have the previously mentioned meanings, in particular the meanings specified as being preferred, and q and q′ are independently of each other 0 or 1, with q+q′ preferably being 0 or 1.

Examples of compounds of the formula Ia.1 are the compounds of the following general formulae Ia.1a, Ia.1b, Ia.1c, Ia.1d, Ia.1e, Ia.1f, Ia.1g, Ia.1h and Ia.1k:

in which R¹, R^(2a), R^(2b), R^(2c), R³, X, Y and R^(b), have the meanings specified in one line in Table 1.

Examples of compounds of the formula Ia.2 are the compounds of the following general formulae Ia.2a, Ia.2b, Ia.2c, Ia.2d and Ia.2e:

in which R¹, R^(2a), R^(2b), R^(2c), R³, X, Y and R^(b) have the meanings specified in one line in Table 1.

TABLE 1 No. R¹ R^(2a) R^(2b) R^(2c) R³ X Y R^(b)  1. H H H H H CH CH CH(CH₃)₂  2. CH₃ H H H H CH CH CH(CH₃)₂  3. CH₂CH₃ H H H H CH CH CH(CH₃)₂  4. CH₂CH═CH₂ H H H H CH CH CH(CH₃)₂  5. CH₂-c-C₃H₅ H H H H CH CH CH(CH₃)₂  6. CH₂CH₂CH₃ H H H H CH CH CH(CH₃)₂  7. H (s)CH₃ H H H CH CH CH(CH₃)₂  8. CH₃ (s)CH₃ H H H CH CH CH(CH₃)₂  9. CH₂CH₃ (s)CH₃ H H H CH CH CH(CH₃)₂  10. CH₂CH═CH₂ (s)CH₃ H H H CH CH CH(CH₃)₂  11. CH₂-c-C₃H₅ (s)CH₃ H H H CH CH CH(CH₃)₂  12. CH₂CH₂CH₃ (s)CH₃ H H H CH CH CH(CH₃)₂  13. CH₃ rac-CH₃ H H H CH CH CH(CH₃)₂  14. CH₂CH═CH₂ rac-CH₃ H H H CH CH CH(CH₃)₂  15. CH₂-c-C₃H₅ rac-CH₃ H H H CH CH CH(CH₃)₂  16. CH₂CH₂CH₃ rac-CH₃ H H H CH CH CH(CH₃)₂  17. CH₃ (R)CH₃ H H H CH CH CH(CH₃)₂  18. CH₂CH═CH₂ (R)CH₃ H H H CH CH CH(CH₃)₂  19. CH₂-c-C₃H₅ (R)CH₃ H H H CH CH CH(CH₃)₂  20. CH₂CH₂CH₃ (R)CH₃ H H H CH CH CH(CH₃)₂  21. CH₃ H CH₃ H H CH CH CH(CH₃)₂  22. CH₂CH═CH₂ H CH₃ H H CH CH CH(CH₃)₂  23. CH₂-c-C₃H₅ H CH₃ H H CH CH CH(CH₃)₂  24. CH₂CH₂CH₃ H CH₃ H H CH CH CH(CH₃)₂  25. CH₃ CH₃ H CH₃ H CH CH CH(CH₃)₂  26. CH₂CH═CH₂ CH₃ H CH₃ H CH CH CH(CH₃)₂  27. CH₂-c-C₃H₅ CH₃ H CH₃ H CH CH CH(CH₃)₂  28. CH₂CH₂CH₃ CH₃ H CH₃ H CH CH CH(CH₃)₂  29. CH₃ CH₃ CH₃ H H CH CH CH(CH₃)₂  30. CH₂CH═CH₂ CH₃ CH₃ H H CH CH CH(CH₃)₂  31. CH₂-c-C₃H₅ CH₃ CH₃ H H CH CH CH(CH₃)₂  32. CH₂CH₂CH₃ CH₃ CH₃ H H CH CH CH(CH₃)₂  33. (s)(CH₂)₃ H H H CH CH CH(CH₃)₂  34. (s)(CH₂)₄ H H H CH CH CH(CH₃)₂  35. rac(CH₂)₃ H H H CH CH CH(CH₃)₂  36. rac (CH₂)₄ H H H CH CH CH(CH₃)₂  37. (R)(CH₂)₃ H H H CH CH CH(CH₃)₂  38. (R)(CH₂)₄ H H H CH CH CH(CH₃)₂  39. CH₂CH═CH₂ H H H H C—Cl CH CH(CH₃)₂  40. CH₂-c-C₃H₅ H H H H C—Cl CH CH(CH₃)₂  41. CH₂CH₂CH₃ H H H H C—Cl CH CH(CH₃)₂  42. CH₂CH═CH₂ (s)CH₃ H H H C—Cl CH CH(CH₃)₂  43. CH₂-c-C₃H₅ (s)CH₃ H H H C—Cl CH CH(CH₃)₂  44. CH₂CH₃ (s)CH₃ H H H C—Cl CH CH(CH₃)₂  45. CH₂CH₂CH₃ (s)CH₃ H H H C—Cl CH CH(CH₃)₂  46. CH₂CH═CH₂ rac-CH₃ H H H C—Cl CH CH(CH₃)₂  47. CH₂-c-C₃H₅ rac-CH₃ H H H C—Cl CH CH(CH₃)₂  48. CH₂CH₂CH₃ rac-CH₃ H H H C—Cl CH CH(CH₃)₂  49. CH₂CH₃ rac-CH₃ H H H C—Cl CH CH(CH₃)₂  50. CH₂CH═CH₂ (R)CH₃ H H H C—Cl CH CH(CH₃)₂  51. CH₂-c-C₃H₅ (R)CH₃ H H H C—Cl CH CH(CH₃)₂  52. CH₂CH₃ (R)CH₃ H H H C—Cl CH CH(CH₃)₂  53. CH₂CH₂CH₃ (R)CH₃ H H H C—Cl CH CH(CH₃)₂  54. CH₂CH═CH₂ H CH₃ H H C—Cl CH CH(CH₃)₂  55. CH₂-c-C₃H₅ H CH₃ H H C—Cl CH CH(CH₃)₂  56. CH₂CH₂CH₃ H CH₃ H H C—Cl CH CH(CH₃)₂  57. CH₂CH═CH₂ CH₃ H CH₃ H C—Cl CH CH(CH₃)₂  58. CH₂-c-C₃H₅ CH₃ H CH₃ H C—Cl CH CH(CH₃)₂  59. CH₂CH₂CH₃ CH₃ H CH₃ H C—Cl CH CH(CH₃)₂  60. CH₂CH═CH₂ CH₃ CH₃ H H C—Cl CH CH(CH₃)₂  61. CH₂-c-C₃H₅ CH₃ CH₃ H H C—Cl CH CH(CH₃)₂  62. CH₂CH₂CH₃ CH₃ CH₃ H H C—Cl CH CH(CH₃)₂  63. (CH₂)₃ H H H C—Cl CH CH(CH₃)₂  64. (CH₂)₄ H H H C—Cl CH CH(CH₃)₂  65. CH₂CH═CH₂ H H H H CH C—Cl CH(CH₃)₂  66. CH₂-c-C₃H₅ H H H H CH C—Cl CH(CH₃)₂  67. CH₂CH₂CH₃ H H H H CH C—Cl CH(CH₃)₂  68. CH₂CH═CH₂ (s)CH₃ H H H CH C—Cl CH(CH₃)₂  69. CH₂-c-C₃H₅ (s)CH₃ H H H CH C—Cl CH(CH₃)₂  70. CH₂CH₂CH₃ (s)CH₃ H H H CH C—Cl CH(CH₃)₂  71. CH₂CH₃ (s)CH₃ H H H CH C—Cl CH(CH₃)₂  72. CH₂CH═CH₂ rac-CH₃ H H H CH C—Cl CH(CH₃)₂  73. CH₂-c-C₃H₅ rac-CH₃ H H H CH C—Cl CH(CH₃)₂  74. CH₂CH₂CH₃ rac-CH₃ H H H CH C—Cl CH(CH₃)₂  75. CH₂CH₃ rac-CH₃ H H H CH C—Cl CH(CH₃)₂  76. CH₂CH═CH₂ (R)CH₃ H H H CH C—Cl CH(CH₃)₂  77. CH₂-c-C₃H₅ (R)CH₃ H H H CH C—Cl CH(CH₃)₂  78. CH₂CH₃ (R)CH₃ H H H CH C—Cl CH(CH₃)₂  79. CH₂CH₂CH₃ (R)CH₃ H H H CH C—Cl CH(CH₃)₂  80. CH₂CH═CH₂ H CH₃ H H CH C—Cl CH(CH₃)₂  81. CH₂-c-C₃H₅ H CH₃ H H CH C—Cl CH(CH₃)₂  82. CH₂CH₂CH₃ H CH₃ H H CH C—Cl CH(CH₃)₂  83. CH₂CH═CH₂ CH₃ H CH₃ H CH C—Cl CH(CH₃)₂  84. CH₂-c-C₃H₅ CH₃ H CH₃ H CH C—Cl CH(CH₃)₂  85. CH₂CH₂CH₃ CH₃ H CH₃ H CH C—Cl CH(CH₃)₂  86. CH₂CH═CH₂ CH₃ CH₃ H H CH C—Cl CH(CH₃)₂  87. CH₂-c-C₃H₅ CH₃ CH₃ H H CH C—Cl CH(CH₃)₂  88. CH₂CH₂CH₃ CH₃ CH₃ H H CH C—Cl CH(CH₃)₂  89. (CH₂)₃ H H H CH C—Cl CH(CH₃)₂  90. (CH₂)₄ H H H CH C—Cl CH(CH₃)₂  91. CH₂CH═CH₂ H H H H C—CH₃ CH CH(CH₃)₂  92. CH₂-c-C₃H₅ H H H H C—CH₃ CH CH(CH₃)₂  93. CH₂CH₂CH₃ H H H H C—CH₃ CH CH(CH₃)₂  94. CH₂CH═CH₂ (s)CH₃ H H H C—CH₃ CH CH(CH₃)₂  95. CH₂-c-C₃H₅ (s)CH₃ H H H C—CH₃ CH CH(CH₃)₂  96. CH₂CH₂CH₃ (s)CH₃ H H H C—CH₃ CH CH(CH₃)₂  97. CH₂CH═CH₂ rac-CH₃ H H H C—CH₃ CH CH(CH₃)₂  98. CH₂-c-C₃H₅ rac-CH₃ H H H C—CH₃ CH CH(CH₃)₂  99. CH₂CH₂CH₃ rac-CH₃ H H H C—CH₃ CH CH(CH₃)₂ 100 CH₂CH═CH₂ (R)CH₃ H H H C—CH₃ CH CH(CH₃)₂ 101 CH₂-c-C₃H₅ (R)CH₃ H H H C—CH₃ CH CH(CH₃)₂ 102 CH₂CH₂CH₃ (R)CH₃ H H H C—CH₃ CH CH(CH₃)₂ 103 CH₂CH═CH₂ H CH₃ H H C—CH₃ CH CH(CH₃)₂ 104 CH₂-c-C₃H₅ H CH₃ H H C—CH₃ CH CH(CH₃)₂ 105 CH₂CH₂CH₃ H CH₃ H H C—CH₃ CH CH(CH₃)₂ 106 CH₂CH═CH₂ CH₃ H CH₃ H C—CH₃ CH CH(CH₃)₂ 107 CH₂-c-C₃H₅ CH₃ H CH₃ H C—CH₃ CH CH(CH₃)₂ 108 CH₂CH₂CH₃ CH₃ H CH₃ H C—CH₃ CH CH(CH₃)₂ 109 CH₂CH═CH₂ CH₃ CH₃ H H C—CH₃ CH CH(CH₃)₂ 110 CH₂-c-C₃H₅ CH₃ CH₃ H H C—CH₃ CH CH(CH₃)₂ 111 CH₂CH₂CH₃ CH₃ CH₃ H H C—CH₃ CH CH(CH₃)₂ 112 (CH₂)₃ H H H C—CH₃ CH CH(CH₃)₂ 113 (CH₂)₄ H H H C—CH₃ CH CH(CH₃)₂ 114 CH₂CH═CH₂ H H H H CH C—CH₃ CH(CH₃)₂ 115 CH₂-c-C₃H₅ H H H H CH C—CH₃ CH(CH₃)₂ 116 CH₂CH₂CH₃ H H H H CH C—CH₃ CH(CH₃)₂ 117 CH₂CH═CH₂ (s)CH₃ H H H CH C—CH₃ CH(CH₃)₂ 118 CH₂-c-C₃H₅ (s)CH₃ H H H CH C—CH₃ CH(CH₃)₂ 119 CH₂CH₂CH₃ (s)CH₃ H H H CH C—CH₃ CH(CH₃)₂ 120 CH₂CH═CH₂ rac-CH₃ H H H CH C—CH₃ CH(CH₃)₂ 121 CH₂-c-C₃H₅ rac-CH₃ H H H CH C—CH₃ CH(CH₃)₂ 122 CH₂CH₂CH₃ rac-CH₃ H H H CH C—CH₃ CH(CH₃)₂ 123 CH₂CH═CH₂ (R)CH₃ H H H CH C—CH₃ CH(CH₃)₂ 124 CH₂-c-C₃H₅ (R)CH₃ H H H CH C—CH₃ CH(CH₃)₂ 125 CH₂CH₂CH₃ (T)CH₃ H H H CH C—CH₃ CH(CH₃)₂ 126 CH₂CH═CH₂ H CH₃ H H CH C—CH₃ CH(CH₃)₂ 127 CH₂-c-C₃H₅ H CH₃ H H CH C—CH₃ CH(CH₃)₂ 128 CH₂CH₂CH₃ H CH₃ H H CH C—CH₃ CH(CH₃)₂ 129 CH₂CH═CH₂ CH₃ H CH₃ H CH C—CH₃ CH(CH₃)₂ 130 CH₂-c-C₃H₅ CH₃ H CH₃ H CH C—CH₃ CH(CH₃)₂ 131 CH₂CH₂CH₃ CH₃ H CH₃ H CH C—CH₃ CH(CH₃)₂ 132 CH₂CH═CH₂ CH₃ CH₃ H H CH C—CH₃ CH(CH₃)₂ 133 CH₂-c-C₃H₅ CH₃ CH₃ H H CH C—CH₃ CH(CH₃)₂ 134 CH₂CH₂CH₃ CH₃ CH₃ H H CH C—CH₃ CH(CH₃)₂ 135 (CH₂)₃ H H H CH C—CH₃ CH(CH₃)₂ 136 (CH₂)₄ H H H CH C—CH₃ CH(CH₃)₂ 137 H H H H H CH CH c-C₃H₅ 138 CH₃ H H H H CH CH c-C₃H₅ 139 CH₂CH₃ H H H H CH CH c-C₃H₅ 140 CH₂CH═CH₂ H H H H CH CH c-C₃H₅ 141 CH₂-c-C₃H₅ H H H H CH CH c-C₃H₅ 142 CH₂CH₂CH₃ H H H H CH CH c-C₃H₅ 143 H (s)CH₃ H H H CH CH c-C₃H₅ 144 CH₃ (s)CH₃ H H H CH CH c-C₃H₅ 145 CH₂CH₃ (s)CH₃ H H H CH CH c-C₃H₅ 146 CH₂CH═CH₂ (s)CH₃ H H H CH CH c-C₃H₅ 147 CH₂-c-C₃H₅ (s)CH₃ H H H CH CH c-C₃H₅ 148 CH₂CH₂CH₃ (s)CH₃ H H H CH CH c-C₃H₅ 149 CH₃ rac-CH₃ H H H CH CH c-C₃H₅ 150 CH₂CH═CH₂ rac-CH₃ H H H CH CH c-C₃H₅ 151 CH₂-c-C₃H₅ rac-CH₃ H H H CH CH c-C₃H₅ 152 CH₂CH₂CH₃ rac-CH₃ H H H CH CH c-C₃H₅ 153 CH₂CH₃ (R)CH₃ H H H CH CH c-C₃H₅ 154 CH₂CH═CH₂ (R)CH₃ H H H CH CH c-C₃H₅ 155 CH₂-c-C₃H₅ (R)CH₃ H H H CH CH c-C₃H₅ 156 CH₂CH₂CH₃ (R)CH₃ H H H CH CH c-C₃H₅ 157 CH₃ H CH₃ H H CH CH c-C₃H₅ 158 CH₂CH═CH₂ H CH₃ H H CH CH c-C₃H₅ 159 CH₂-c-C₃H₅ H CH₃ H H CH CH c-C₃H₅ 160 CH₂CH₂CH₃ H CH₃ H H CH CH c-C₃H₅ 161 CH₃ CH₃ H CH₃ H CH CH c-C₃H₅ 162 CH₂CH═CH₂ CH₃ H CH₃ H CH CH c-C₃H₅ 163 CH₂-c-C₃H₅ CH₃ H CH₃ H CH CH c-C₃H₅ 164 CH₂CH₂CH₃ CH₃ H CH₃ H CH CH c-C₃H₅ 165 CH₃ CH₃ CH₃ H H CH CH c-C₃H₅ 166 CH₂CH═CH₂ CH₃ CH₃ H H CH CH c-C₃H₅ 167 CH₂-c-C₃H₅ CH₃ CH₃ H H CH CH c-C₃H₅ 168 CH₂CH₂CH₃ CH₃ CH₃ H H CH CH c-C₃H₅ 169 (s)(CH₂)₃ H H H CH CH c-C₃H₅ 170 (s)(CH₂)₄ H H H CH CH c-C₃H₅ 171 rac(CH₂)₃ H H H CH CH c-C₃H₅ 172 rac(CH₂)₄ H H H CH CH c-C₃H₅ 173 (R)(CH₂)₃ H H H CH CH c-C₃H₅ 174 (R)(CH₂)₄ H H H CH CH c-C₃H₅ 175 CH₂CH═CH₂ H H H H CH C—Cl c-C₃H₅ 176 CH₂-c-C₃H₅ H H H H CH C—Cl c-C₃H₅ 177 CH₂CH₂CH₃ H H H H CH C—Cl c-C₃H₅ 178 CH₂CH═CH₂ (s)CH₃ H H H CH C—Cl c-C₃H₅ 179 CH₂-c-C₃H₅ (s)CH₃ H H H CH C—Cl c-C₃H₅ 180 CH₂CH₃ (s)CH₃ H H H CH C—Cl c-C₃H₅ 181 CH₂CH₂CH₃ (s)CH₃ H H H CH C—Cl c-C₃H₅ 182 CH₂CH═CH₂ rac-CH₃ H H H CH C—Cl c-C₃H₅ 183 CH₂-c-C₃H₅ rac-CH₃ H H H CH C—Cl c-C₃H₅ 184 CH₂CH₃ rac-CH₃ H H H CH C—Cl c-C₃H₅ 185 CH₂CH₂CH₃ rac-CH₃ H H H CH C—Cl c-C₃H₅ 186 CH₂CH═CH₂ (R)CH₃ H H H CH C—Cl c-C₃H₅ 187 CH₂-c-C₃H₅ (R)CH₃ H H H CH C—Cl c-C₃H₅ 188 CH₂CH₃ (R)CH₃ H H H CH C—Cl c-C₃H₅ 189 CH₂CH₂CH₃ (R)CH₃ H H H CH C—Cl c-C₃H₅ 190 CH₂CH═CH₂ H H H H CH C—CH₃ c-C₃H₅ 191 CH₂-c-C₃H₅ H H H H CH C—CH₃ c-C₃H₅ 192 CH₂CH₂CH₃ H H H H CH C—CH₃ c-C₃H₅ 193 CH₂CH═CH₂ (s)CH₃ H H H CH C—CH₃ c-C₃H₅ 194 CH₂-c-C₃H₅ (s)CH₃ H H H CH C—CH₃ c-C₃H₅ 195 CH₂CH₃ (s)CH₃ H H H CH C—CH₃ c-C₃H₅ 196 CH₂CH₂CH₃ (s)CH₃ H H H CH C—CH₃ c-C₃H₅ 197 CH₂CH═CH₂ rac-CH₃ H H H CH C—CH₃ c-C₃H₅ 198 CH₂-c-C₃H₅ rac-CH₃ H H H CH C—CH₃ c-C₃H₅ 199 CH₂CH₃ rac-CH₃ H H H CH C—CH₃ c-C₃H₅ 200 CH₂CH₂CH₃ rac-CH₃ H H H CH C—CH₃ c-C₃H₅ 201 CH₂CH═CH₂ (R)CH₃ H H H CH C—CH₃ c-C₃H₅ 202 CH₂-c-C₃H₅ (R)CH₃ H H H CH C—CH₃ c-C₃H₅ 203 CH₂CH₃ (R)CH₃ H H H CH C—CH₃ c-C₃H₅ 204 CH₂CH₂CH₃ (R)CH₃ H H H CH C—CH₃ c-C₃H₅ 205 CH₂CH═CH₂ H H H H C—Cl CH c-C₃H₅ 206 CH₂-c-C₃H₅ H H H H C—Cl CH c-C₃H₅ 207 CH₂CH₂CH₃ H H H H C—Cl CH c-C₃H₅ 208 CH₂CH═CH₂ (s)CH₃ H H H C—Cl CH c-C₃H₅ 209 CH₂-c-C₃H₅ (s)CH₃ H H H C—Cl CH c-C₃H₅ 210 CH₂CH₂CH₃ (s)CH₃ H H H C—Cl CH c-C₃H₅ 211 CH₂CH═CH₂ rac-CH₃ H H H C—Cl CH c-C₃H₅ 212 CH₂-c-C₃H₅ rac-CH₃ H H H C—Cl CH c-C₃H₅ 213 CH₂CH₂CH₃ rac-CH₃ H H H C—Cl CH c-C₃H₅ 214 CH₂CH═CH₂ H H H H C—CH₃ CH c-C₃H₅ 215 CH₂-c-C₃H₅ H H H H C—CH₃ CH c-C₃H₅ 216 CH₂CH₂CH₃ H H H H C—CH₃ CH c-C₃H₅ 217 CH₂CH═CH₂ (s)CH₃ H H H C—CH₃ CH c-C₃H₅ 218 CH₂-c-C₃H₅ (s)CH₃ H H H C—CH₃ CH c-C₃H₅ 219 CH₂CH₃ (s)CH₃ H H H C—CH₃ CH c-C₃H₅ 220 CH₂CH₂CH₃ (s)CH₃ H H H C—CH₃ CH c-C₃H₅ 221 CH₂CH═CH₂ rac-CH₃ H H H C—CH₃ CH c-C₃H₅ 222 CH₂-c-C₃H₅ rac-CH₃ H H H C—CH₃ CH c-C₃H₅ 223 CH₂CH₂CH₃ rac-CH₃ H H H C—CH₃ CH c-C₃H₅ 224 CH₂CH═CH₂ (R)CH₃ H H H C—CH₃ CH c-C₃H₅ 225 CH₂-c-C₃H₅ (R)CH₃ H H H C—CH₃ CH c-C₃H₅ 226 CH₂CH₂CH₃ (R)CH₃ H H H C—CH₃ CH c-C₃H₅ 227 H H H H H CH CH C₂H₅ 228 CH₃ H H H H CH CH C₂H₅ 229 CH₂CH₃ H H H H CH CH C₂H₅ 230 CH₂CH═CH₂ H H H H CH CH C₂H₅ 231 CH₂-c-C₃H₅ H H H H CH CH C₂H₅ 232 CH₂CH₂CH₃ H H H H CH CH C₂H₅ 233 H (s)CH₃ H H H CH CH C₂H₅ 234 CH₃ (s)CH₃ H H H CH CH C₂H₅ 235 CH₂CH₃ (s)CH₃ H H H CH CH C₂H₅ 236 CH₂CH═CH₂ (s)CH₃ H H H CH CH C₂H₅ 237 CH₂-c-C₃H₅ (s)CH₃ H H H CH CH C₂H₅ 238 CH₂CH₂CH₃ (s)CH₃ H H H CH CH C₂H₅ 239 CH₃ rac-CH₃ H H H CH CH C₂H₅ 240 CH₂CH═CH₂ rac-CH₃ H H H CH CH C₂H₅ 241 CH₂-c-C₃H₅ rac-CH₃ H H H CH CH C₂H₅ 242 CH₂CH₂CH₃ rac-CH₃ H H H CH CH C₂H₅ 243 CH₃ (R)CH₃ H H H CH CH C₂H₅ 244 CH₂CH₃ (R)CH₃ H H H CH CH C₂H₅ 245 CH₂CH═CH₂ (R)CH₃ H H H CH CH C₂H₅ 246 CH₂-c-C₃H₅ (R)CH₃ H H H CH CH C₂H₅ 247 CH₂CH₂CH₃ (R)CH₃ H H H CH CH C₂H₅ 248 CH₃ H CH₃ H H CH CH C₂H₅ 249 CH₂CH═CH₂ H CH₃ H H CH CH C₂H₅ 250 CH₂-c-C₃H₅ H CH₃ H H CH CH C₂H₅ 251 CH₂CH₂CH₃ H CH₃ H H CH CH C₂H₅ 252 CH₃ CH₃ H CH₃ H CH CH C₂H₅ 253 CH₂CH═CH₂ CH₃ H CH₃ H CH CH C₂H₅ 254 CH₂-c-C₃H₅ CH₃ H CH₃ H CH CH C₂H₅ 255 CH₂CH₂CH₃ CH₃ H CH₃ H CH CH C₂H₅ 256 CH₃ CH₃ CH₃ H H CH CH C₂H₅ 257 CH₂CH═CH₂ CH₃ CH₃ H H CH CH C₂H₅ 258 CH₂-c-C₃H₅ CH₃ CH₃ H H CH CH C₂H₅ 259 CH₂CH₂CH₃ CH₃ CH₃ H H CH CH C₂H₅ 260 (s)(CH₂)₃ H H H CH CH C₂H₅ 261 (s)(CH₂)₄ H H H CH CH C₂H₅ 262 rac(CH₂)₃ H H H CH CH C₂H₅ 263 rac(CH₂)₄ H H H CH CH C₂H₅ 264 (R)(CH₂)₃ H H H CH CH C₂H₅ 265 (R)(CH₂)₄ H H H CH CH C₂H₅ 266 H H H H H CH CH CH₃ 267 CH₃ H H H H CH CH CH₃ 268 CH₂CH₃ H H H H CH CH CH₃ 269 CH₂CH═CH₂ H H H H CH CH CH₃ 270 CH₂-c-C₃H₅ H H H H CH CH CH₃ 271 CH₂CH₂CH₃ H H H H CH CH CH₃ 272 H (s)CH₃ H H H CH CH CH₃ 273 CH₃ (s)CH₃ H H H CH CH CH₃ 274 CH₂CH₃ (s)CH₃ H H H CH CH CH₃ 275 CH₂CH═CH₂ (s)CH₃ H H H CH CH CH₃ 276 CH₂-c-C₃H₅ (s)CH₃ H H H CH CH CH₃ 277 CH₂CH₂CH₃ (s)CH₃ H H H CH CH CH₃ 278 CH₂CH═CH₂ rac-CH₃ H H H CH CH CH₃ 279 CH₂CH₂CH₃ rac-CH₃ H H H CH CH CH₃ 280 CH₂CH₃ (R)CH₃ H H H CH CH CH₃ 281 CH₂CH═CH₂ (R)CH₃ H H H CH CH CH₃ 282 CH₂-c-C₃H₅ (R)CH₃ H H H CH CH CH₃ 283 CH₂CH₂CH₃ (R)CH₃ H H H CH CH CH₃ 284 CH₂CH═CH₂ H CH₃ H H CH CH CH₃ 285 CH₂CH₂CH₃ H CH₃ H H CH CH CH₃ 286 CH₂CH═CH₂ CH₃ H CH₃ H CH CH CH₃ 287 CH₂CH₂CH₃ CH₃ H CH₃ H CH CH CH₃ 288 CH₂CH═CH₂ CH₃ CH₃ H H CH CH CH₃ 289 CH₂CH₂CH₃ CH₃ CH₃ H H CH CH CH₃ 290 (s)(CH₂)₃ H H H CH CH CH₃ 291 (s)(CH₂)₄ H H H CH CH CH₃ 292 rac(CH₂)₃ H H H CH CH CH₃ 293 rac(CH₂)₄ H H H CH CH CH₃ 294 (R)(CH₂)₃ H H H CH CH CH₃ 295 (R)(CH₂)₄ H H H CH CH CH₃ 296 H H H H H N CH CH(CH₃)₂ 297 CH₃ H H H H N CH CH(CH₃)₂ 298 CH₂CH₃ H H H H N CH CH(CH₃)₂ 299 CH₂CH═CH₂ H H H H N CH CH(CH₃)₂ 300 CH₂-c-C₃H₅ H H H H N CH CH(CH₃)₂ 301 CH₂CH₂CH₃ H H H H N CH CH(CH₃)₂ 302 H (s)CH₃ H H H N CH CH(CH₃)₂ 303 CH₃ (s)CH₃ H H H N CH CH(CH₃)₂ 304 CH₂CH₃ (s)CH₃ H H H N CH CH(CH₃)₂ 305 CH₂CH═CH₂ (s)CH₃ H H H N CH CH(CH₃)₂ 306 CH₂-c-C₃H₅ (s)CH₃ H H H N CH CH(CH₃)₂ 307 CH₂CH₂CH₃ (s)CH₃ H H H N CH CH(CH₃)₂ 308 CH₂CH═CH₂ rac-CH₃ H H H N CH CH(CH₃)₂ 309 CH₂CH₂CH₃ rac-CH₃ H H H N CH CH(CH₃)₂ 310 CH₂CH₃ (R)CH₃ H H H N CH CH(CH₃)₂ 311 CH₂CH═CH₂ (R)CH₃ H H H N CH CH(CH₃)₂ 312 CH₂-c-C₃H₅ (R)CH₃ H H H N CH CH(CH₃)₂ 313 CH₂CH₂CH₃ (R)CH₃ H H H N CH CH(CH₃)₂ 314 (s)(CH₂)₃ H H H N CH CH(CH₃)₂ 315 (s)(CH₂)₄ H H H N CH CH(CH₃)₂ 316 rac(CH₂)₃ H H H N CH CH(CH₃)₂ 317 rac(CH₂)₄ H H H N CH CH(CH₃)₂ 318 (R)(CH₂)₃ H H H N CH CH(CH₃)₂ 319 (R)(CH₂)₄ H H H N CH CH(CH₃)₂ 320 H H H H H N CH CH═CH₂ 321 CH₃ H H H H N CH CH═CH₂ 322 CH₂CH₃ H H H H N CH CH═CH₂ 323 CH₂CH═CH₂ H H H H N CH CH═CH₂ 324 CH₂-c-C₃H₅ H H H H N CH CH═CH₂ 325 CH₂CH₂CH₃ H H H H N CH CH═CH₂ 326 H (s)CH₃ H H H N CH CH═CH₂ 327 CH₃ (s)CH₃ H H H N CH CH═CH₂ 328 CH₂CH₃ (s)CH₃ H H H N CH CH═CH₂ 329 CH₂CH═CH₂ (s)CH₃ H H H N CH CH═CH₂ 330 CH₂-c-C₃H₅ (s)CH₃ H H H N CH CH═CH₂ 331 CH₂CH₂CH₃ (s)CH₃ H H H N CH CH═CH₂ 332 CH₂CH═CH₂ (R)CH₃ H H H N CH CH═CH₂ 333 CH₂CH₂CH₃ (R)CH₃ H H H N CH CH═CH₂ 334 CH₂CH═CH₂ rac-CH₃ H H H N CH CH═CH₂ 335 CH₂CH₂CH₃ rac-CH₃ H H H N CH CH═CH₂ 336 H H H H H N CH c-C₃H₅ 337 CH₃ H H H H N CH c-C₃H₅ 338 CH₂CH₃ H H H H N CH c-C₃H₅ 339 CH₂CH═CH₂ H H H H N CH c-C₃H₅ 340 CH₂-c-C₃H₅ H H H H N CH c-C₃H₅ 341 CH₂CH₂CH₃ H H H H N CH c-C₃H₅ 342 H (s)CH₃ H H H N CH c-C₃H₅ 343 CH₃ (s)CH₃ H H H N CH c-C₃H₅ 344 CH₂CH₃ (s)CH₃ H H H N CH c-C₃H₅ 345 CH₂CH═CH₂ (s)CH₃ H H H N CH c-C₃H₅ 346 CH₂-c-C₃H₅ (s)CH₃ H H H N CH c-C₃H₅ 347 CH₂CH₂CH₃ (s)CH₃ H H H N CH c-C₃H₅ 348 CH₂CH₃ (R)CH₃ H H H N CH c-C₃H₅ 349 CH₂CH═CH₂ (R)CH₃ H H H N CH c-C₃H₅ 350 CH₂CH₂CH₃ (R)CH₃ H H H N CH c-C₃H₅ 351 CH₂CH═CH₂ rac-CH₃ H H H N CH c-C₃H₅ 352 CH₂CH₂CH₃ rac-CH₃ H H H N CH c-C₃H₅ 353 H H H H H N CH CH₃ 354 CH₃ H H H H N CH CH₃ 355 CH₂CH₃ H H H H N CH CH₃ 356 CH₂CH═CH₂ H H H H N CH CH₃ 357 CH₂-c-C₃H₅ H H H H N CH CH₃ 358 CH₂CH₂CH₃ H H H H N CH CH₃ 359 H (s)CH₃ H H H N CH CH₃ 360 CH₃ (s)CH₃ H H H N CH CH₃ 361 CH₂CH₃ (s)CH₃ H H H N CH CH₃ 362 CH₂CH═CH₂ (s)CH₃ H H H N CH CH₃ 363 CH₂-c-C₃H₅ (s)CH₃ H H H N CH CH₃ 364 CH₂CH₂CH₃ (s)CH₃ H H H N CH CH₃ 365 CH₂CH═CH₂ (R)CH₃ H H H N CH CH₃ 366 CH₂CH₂CH₃ (R)CH₃ H H H N CH CH₃ 367 CH₂CH═CH₂ rac-CH₃ H H H N CH CH₃ 368 CH₂CH₂CH₃ rac-CH₃ H H H N CH CH₃ 369 H H H H H N CH CF₃ 370 CH₃ H H H H N CH CF₃ 371 CH₂CH₃ H H H H N CH CF₃ 372 CH₂CH═CH₂ H H H H N CH CF₃ 373 CH₂-c-C₃H₅ H H H H N CH CF₃ 374 CH₂CH₂CH₃ H H H H N CH CF₃ 375 H (s)CH₃ H H H N CH CF₃ 376 CH₃ (s)CH₃ H H H N CH CF₃ 377 CH₂CH₃ (s)CH₃ H H H N CH CF₃ 378 CH₂CH═CH₂ (s)CH₃ H H H N CH CF₃ 379 CH₂-c-C₃H₅ (s)CH₃ H H H N CH CF₃ 380 CH₂CH₂CH₃ (s)CH₃ H H H N CH CF₃ 381 CH₂CH═CH₂ (R)CH₃ H H H N CH CF₃ 382 CH₂CH₂CH₃ (R)CH₃ H H H N CH CF₃ 383 CH₂CH═CH₂ rac-CH₃ H H H N CH CF₃ 384 CH₂CH₂CH₃ rac-CH₃ H H H N CH CF₃ 385 H H H H H CH N CH(CH₃)₂ 386 CH₃ H H H H CH N CH(CH₃)₂ 387 CH₂CH₃ H H H H CH N CH(CH₃)₂ 388 CH₂CH═CH₂ H H H H CH N CH(CH₃)₂ 389 CH₂-c-C₃H₅ H H H H CH N CH(CH₃)₂ 390 CH₂CH₂CH₃ H H H H CH N CH(CH₃)₂ 391 H (s)CH₃ H H H CH N CH(CH₃)₂ 392 CH₃ (s)CH₃ H H H CH N CH(CH₃)₂ 393 CH₂CH₃ (s)CH₃ H H H CH N CH(CH₃)₂ 394 CH₂CH═CH₂ (s)CH₃ H H H CH N CH(CH₃)₂ 395 CH₂-c-C₃H₅ (s)CH₃ H H H CH N CH(CH₃)₂ 396 CH₂CH₂CH₃ (s)CH₃ H H H CH N CH(CH₃)₂ 397 CH₂CH═CH₂ rac-CH₃ H H H CH N CH(CH₃)₂ 398 CH₂CH₂CH₃ rac-CH₃ H H H CH N CH(CH₃)₂ 399 CH₂CH₃ (R)CH₃ H H H CH N CH(CH₃)₂ 400 CH₂CH═CH₂ (R)CH₃ H H H CH N CH(CH₃)₂ 401 CH₂-c-C₃H₅ (R)CH₃ H H H CH N CH(CH₃)₂ 402 CH₂CH₂CH₃ (R)CH₃ H H H CH N CH(CH₃)₂ 403 H H H H H CH N CH═CH₂ 404 CH₃ H H H H CH N CH═CH₂ 405 CH₂CH₃ H H H H CH N CH═CH₂ 406 CH₂CH═CH₂ H H H H CH N CH═CH₂ 407 CH₂-c-C₃H₅ H H H H CH N CH═CH₂ 408 CH₂CH₂CH₃ H H H H CH N CH═CH₂ 409 H (s)CH₃ H H H CH N CH═CH₂ 410 CH₃ (s)CH₃ H H H CH N CH═CH₂ 411 CH₂CH₃ (s)CH₃ H H H CH N CH═CH₂ 412 CH₂CH═CH₂ (s)CH₃ H H H CH N CH═CH₂ 413 CH₂-c-C₃H₅ (s)CH₃ H H H CH N CH═CH₂ 414 CH₂CH₂CH₃ (s)CH₃ H H H CH N CH═CH₂ 415 CH₂CH═CH₂ rac-CH₃ H H H CH N CH═CH₂ 416 CH₂CH₂CH₃ rac-CH₃ H H H CH N CH═CH₂ 417 CH₂CH₃ (R)CH₃ H H H CH N CH═CH₂ 418 CH₂CH═CH₂ (R)CH₃ H H H CH N CH═CH₂ 419 CH₂-c-C₃H₅ (R)CH₃ H H H CH N CH═CH₂ 420 CH₂CH₂CH₃ (R)CH₃ H H H CH N CH═CH₂ 421 H H H H H CH N c-C₃H₅ 422 CH₃ H H H H CH N c-C₃H₅ 423 CH₂CH₃ H H H H CH N c-C₃H₅ 424 CH₂CH═CH₂ H H H H CH N c-C₃H₅ 425 CH₂-c-C₃H₅ H H H H CH N c-C₃H₅ 426 CH₂CH₂CH₃ H H H H CH N c-C₃H₅ 427 H (s)CH₃ H H H CH N c-C₃H₅ 428 CH₃ (s)CH₃ H H H CH N c-C₃H₅ 429 CH₂CH₃ (s)CH₃ H H H CH N c-C₃H₅ 430 CH₂CH═CH₂ (s)CH₃ H H H CH N c-C₃H₅ 431 CH₂-c-C₃H₅ (s)CH₃ H H H CH N c-C₃H₅ 432 CH₂CH₂CH₃ (s)CH₃ H H H CH N c-C₃H₅ 433 CH₂CH═CH₂ rac-CH₃ H H H CH N c-C₃H₅ 434 CH₂CH₂CH₃ rac-CH₃ H H H CH N c-C₃H₅ 435 CH₂CH₃ (R)CH₃ H H H CH N c-C₃H₅ 436 CH₂CH═CH₂ (R)CH₃ H H H CH N c-C₃H₅ 437 CH₂-c-C₃H₅ (R)CH₃ H H H CH N c-C₃H₅ 438 CH₂CH₂CH₃ (R)CH₃ H H H CH N c-C₃H₅ 439 H H H H H CH N CH₃ 440 CH₃ H H H H CH N CH₃ 441 CH₂CH₃ H H H H CH N CH₃ 442 CH₂CH═CH₂ H H H H CH N CH₃ 443 CH₂-c-C₃H₅ H H H H CH N CH₃ 444 CH₂CH₂CH₃ H H H H CH N CH₃ 445 H (s)CH₃ H H H CH N CH₃ 446 CH₃ (s)CH₃ H H H CH N CH₃ 447 CH₂CH₃ (s)CH₃ H H H CH N CH₃ 448 CH₂CH═CH₂ (s)CH₃ H H H CH N CH₃ 449 CH₂-c-C₃H₅ (s)CH₃ H H H CH N CH₃ 450 CH₂CH₂CH₃ (s)CH₃ H H H CH N CH₃ 451 CH₂CH═CH₂ rac-CH₃ H H H CH N CH₃ 452 CH₂CH₂CH₃ rac-CH₃ H H H CH N CH₃ 453 CH₂CH₃ (R)CH₃ H H H CH N CH₃ 454 CH₂CH═CH₂ (R)CH₃ H H H CH N CH₃ 455 CH₂-c-C₃H₅ (R)CH₃ H H H CH N CH₃ 456 CH₂CH₂CH₃ (R)CH₃ H H H CH N CH₃ 457 H H H H H CH N CF₃ 458 CH₃ H H H H CH N CF₃ 459 CH₂CH₃ H H H H CH N CF₃ 460 CH₂CH═CH₂ H H H H CH N CF₃ 461 CH₂-c-C₃H₅ H H H H CH N CF₃ 462 CH₂CH₂CH₃ H H H H CH N CF₃ 463 H (s)CH₃ H H H CH N CF₃ 464 CH₃ (s)CH₃ H H H CH N CF₃ 465 CH₂CH₃ (s)CH₃ H H H CH N CF₃ 466 CH₂CH═CH₂ (s)CH₃ H H H CH N CF₃ 467 CH₂-c-C₃H₅ (s)CH₃ H H H CH N CF₃ 468 CH₂CH₂CH₃ (s)CH₃ H H H CH N CF₃ 469 CH₂CH₃ (R)CH₃ H H H CH N CF₃ 470 CH₂CH═CH₂ (R)CH₃ H H H CH N CF₃ 471 CH₂-c-C₃H₅ (R)CH₃ H H H CH N CF₃ 472 CH₂CH₂CH₃ (R)CH₃ H H H CH N CF₃ 473 CH₂CH═CH₂ rac-CH₃ H H H CH N CF₃ 474 CH₂CH₂CH₃ rac-CH₃ H H H CH N CF₃ 475 H H H H CH₃ CH CH CH(CH₃)₂ 476 CH₃ H H H CH₃ CH CH CH(CH₃)₂ 477 CH₂CH₃ H H H CH₃ CH CH CH(CH₃)₂ 478 CH₂CH═CH₂ H H H CH₃ CH CH CH(CH₃)₂ 479 CH₂-c-C₃H₅ H H H CH₃ CH CH CH(CH₃)₂ 480 CH₂CH₂CH₃ H H H CH₃ CH CH CH(CH₃)₂ 481 H (s)CH₃ H H CH₃ CH CH CH(CH₃)₂ 482 CH₃ (s)CH₃ H H CH₃ CH CH CH(CH₃)₂ 483 CH₂CH₃ (s)CH₃ H H CH₃ CH CH CH(CH₃)₂ 484 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH CH CH(CH₃)₂ 485 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH CH CH(CH₃)₂ 486 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH CH CH(CH₃)₂ 487 CH₃ rac-CH₃ H H CH₃ CH CH CH(CH₃)₂ 488 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH CH CH(CH₃)₂ 489 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ CH CH CH(CH₃)₂ 490 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH CH CH(CH₃)₂ 491 CH₃ (R)CH₃ H H CH₃ CH CH CH(CH₃)₂ 492 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH CH CH(CH₃)₂ 493 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH CH CH(CH₃)₂ 494 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH CH CH(CH₃)₂ 495 CH₃ H CH₃ H CH₃ CH CH CH(CH₃)₂ 496 CH₂CH═CH₂ H CH₃ H CH₃ CH CH CH(CH₃)₂ 497 CH₂-c-C₃H₅ H CH₃ H CH₃ CH CH CH(CH₃)₂ 498 CH₂CH₂CH₃ H CH₃ H CH₃ CH CH CH(CH₃)₂ 499 CH₃ CH₃ H CH₃ CH₃ CH CH CH(CH₃)₂ 500 CH₂CH═CH₂ CH₃ H CH₃ CH₃ CH CH CH(CH₃)₂ 501 CH₂-c-C₃H₅ CH₃ H CH₃ CH₃ CH CH CH(CH₃)₂ 502 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ CH CH CH(CH₃)₂ 503 CH₃ CH₃ CH₃ H CH₃ CH CH CH(CH₃)₂ 504 CH₂CH═CH₂ CH₃ CH₃ H CH₃ CH CH CH(CH₃)₂ 505 CH₂-c-C₃H₅ CH₃ CH₃ H CH₃ CH CH CH(CH₃)₂ 506 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ CH CH CH(CH₃)₂ 507 (S)(CH₂)₃ H H CH₃ CH CH CH(CH₃)₂ 508 (S)(CH₂)₄ H H CH₃ CH CH CH(CH₃)₂ 509 rac(CH₂)₃ H H CH₃ CH CH CH(CH₃)₂ 510 rac(CH₂)₄ H H CH₃ CH CH CH(CH₃)₂ 511 (R)(CH₂)₃ H H CH₃ CH CH CH(CH₃)₂ 512 (R)(CH₂)₄ H H CH₃ CH CH CH(CH₃)₂ 513 CH₂CH═CH₂ H H H CH₃ C—Cl CH CH(CH₃)₂ 514 CH₂-c-C₃H₅ H H H CH₃ C—Cl CH CH(CH₃)₂ 515 CH₂CH₂CH₃ H H H CH₃ C—Cl CH CH(CH₃)₂ 516 CH₂CH═CH₂ (s)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 517 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 518 CH₂CH₃ (s)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 519 CH₂CH₂CH₃ (s)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 520 CH₂CH═CH₂ rac-CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 521 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 522 CH₂CH₃ rac-CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 523 CH₂CH₂CH₃ rac-CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 524 CH₂CH═CH₂ (R)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 525 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 526 CH₂CH₂CH₃ (R)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 527 CH₂CH₃ (R)CH₃ H H CH₃ C—Cl CH CH(CH₃)₂ 528 CH₂CH═CH₂ H CH₃ H CH₃ C—Cl CH CH(CH₃)₂ 529 CH₂-c-C₃H₅ H CH₃ H CH₃ C—Cl CH CH(CH₃)₂ 530 CH₂CH₂CH₃ H CH₃ H CH₃ C—Cl CH CH(CH₃)₂ 531 CH₂CH═CH₂ CH₃ H CH₃ CH₃ C—Cl CH CH(CH₃)₂ 532 CH₂-c-C₃H₅ CH₃ H CH₃ CH₃ C—Cl CH CH(CH₃)₂ 533 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ C—Cl CH CH(CH₃)₂ 534 CH₂CH═CH₂ CH₃ CH₃ H CH₃ C—Cl CH CH(CH₃)₂ 535 CH₂-c-C₃H₅ CH₃ CH₃ H CH₃ C—Cl CH CH(CH₃)₂ 536 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ C—Cl CH CH(CH₃)₂ 537 (CH₂)₃ H H CH₃ C—Cl CH CH(CH₃)₂ 538 (CH₂)₄ H H CH₃ C—Cl CH CH(CH₃)₂ 539 CH₂CH═CH₂ H H H CH₃ CH C—Cl CH(CH₃)₂ 540 CH₂-c-C₃H₅ H H H CH₃ CH C—Cl CH(CH₃)₂ 541 CH₂CH₂CH₃ H H H CH₃ CH C—Cl CH(CH₃)₂ 542 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 543 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 544 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 545 CH₂CH₃ (s)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 546 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 547 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 548 CH₂CH₃ rac-CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 549 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 550 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 551 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 552 CH₂CH₃ (R)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 553 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH C—Cl CH(CH₃)₂ 554 CH₂CH═CH₂ H CH₃ H CH₃ CH C—Cl CH(CH₃)₂ 555 CH₂-c-C₃H₅ H CH₃ H CH₃ CH C—Cl CH(CH₃)₂ 556 CH₂CH₂CH₃ H CH₃ H CH₃ CH C—Cl CH(CH₃)₂ 557 CH₂CH═CH₂ CH₃ H CH₃ CH₃ CH C—Cl CH(CH₃)₂ 558 CH₂-c-C₃H₅ CH₃ H CH₃ CH₃ CH C—Cl CH(CH₃)₂ 559 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ CH C—Cl CH(CH₃)₂ 560 CH₂CH═CH₂ CH₃ CH₃ H CH₃ CH C—Cl CH(CH₃)₂ 561 CH₂-c-C₃H₅ CH₃ CH₃ H CH₃ CH C—Cl CH(CH₃)₂ 562 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ CH C—Cl CH(CH₃)₂ 563 (CH₂)₃ H H CH₃ CH C—Cl CH(CH₃)₂ 564 (CH₂)₄ H H CH₃ CH C—Cl CH(CH₃)₂ 565 CH₂CH═CH₂ H H H CH₃ C—CH₃ CH CH(CH₃)₂ 566 CH₂-c-C₃H₅ H H H CH₃ C—CH₃ CH CH(CH₃)₂ 567 CH₂CH₂CH₃ H H H CH₃ C—CH₃ CH CH(CH₃)₂ 568 CH₂CH═CH₂ (s)CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 569 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 570 CH₂CH₂CH₃ (s)CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 571 CH₂CH═CH₂ rac-CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 572 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 573 CH₂CH₂CH₃ rac-CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 574 CH₂CH═CH₂ (R)CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 575 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 576 CH₂CH₂CH₃ (R)CH₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 577 CH₂CH═CH₂ H CH₃ H CH₃ C—CH₃ CH CH(CH₃)₂ 578 CH₂-c-C₃H₅ H CH₃ H CH₃ C—CH₃ CH CH(CH₃)₂ 579 CH₂CH₂CH₃ H CH₃ H CH₃ C—CH₃ CH CH(CH₃)₂ 580 CH₂CH═CH₂ CH₃ H CH₃ CH₃ C—CH₃ CH CH(CH₃)₂ 581 CH₂-c-C₃H₅ CH₃ H CH₃ CH₃ C—CH₃ CH CH(CH₃)₂ 582 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ C—CH₃ CH CH(CH₃)₂ 583 CH₂CH═CH₂ CH₃ CH₃ H CH₃ C—CH₃ CH CH(CH₃)₂ 584 CH₂-c-C₃H₅ CH₃ CH₃ H CH₃ C—CH₃ CH CH(CH₃)₂ 585 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ C—CH₃ CH CH(CH₃)₂ 586 (CH₂)₃ H H CH₃ C—CH₃ CH CH(CH₃)₂ 587 (CH₂)₄ H H CH₃ C—CH₃ CH CH(CH₃)₂ 588 CH₂CH═CH₂ H H H CH₃ CH C—CH₃ CH(CH₃)₂ 589 CH₂-c-C₃H₅ H H H CH₃ CH C—CH₃ CH(CH₃)₂ 590 CH₂CH₂CH₃ H H H CH₃ CH C—CH₃ CH(CH₃)₂ 591 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 592 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 593 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 594 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 595 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 596 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 597 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 598 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 599 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 600 CH₂CH═CH₂ H CH₃ H CH₃ CH C—CH₃ CH(CH₃)₂ 601 CH₂-c-C₃H₅ H CH₃ H CH₃ CH C—CH₃ CH(CH₃)₂ 602 CH₂CH₂CH₃ H CH₃ H CH₃ CH C—CH₃ CH(CH₃)₂ 603 CH₂CH═CH₂ CH₃ H CH₃ CH₃ CH C—CH₃ CH(CH₃)₂ 604 CH₂-c-C₃H₅ CH₃ H CH₃ CH₃ CH C—CH₃ CH(CH₃)₂ 605 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ CH C—CH₃ CH(CH₃)₂ 606 CH₂CH═CH₂ CH₃ CH₃ H CH₃ CH C—CH₃ CH(CH₃)₂ 607 CH₂-c-C₃H₅ CH₃ CH₃ H CH₃ CH C—CH₃ CH(CH₃)₂ 608 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ CH C—CH₃ CH(CH₃)₂ 609 (CH₂)₃ H H CH₃ CH C—CH₃ CH(CH₃)₂ 610 (CH₂)₄ H H CH₃ CH C—CH₃ CH(CH₃)₂ 611 H H H H CH₃ CH CH c-C₃H₅ 612 CH₃ H H H CH₃ CH CH c-C₃H₅ 613 CH₂CH₃ H H H CH₃ CH CH c-C₃H₅ 614 CH₂CH═CH₂ H H H CH₃ CH CH c-C₃H₅ 615 CH₂-c-C₃H₅ H H H CH₃ CH CH c-C₃H₅ 616 CH₂CH₂CH₃ H H H CH₃ CH CH c-C₃H₅ 617 H (s)CH₃ H H CH₃ CH CH c-C₃H₅ 618 CH₃ (s)CH₃ H H CH₃ CH CH c-C₃H₅ 619 CH₂CH₃ (s)CH₃ H H CH₃ CH CH c-C₃H₅ 620 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH CH c-C₃H₅ 621 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH CH c-C₃H₅ 622 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH CH c-C₃H₅ 623 CH₃ rac-CH₃ H H CH₃ CH CH c-C₃H₅ 624 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH CH c-C₃H₅ 625 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ CH CH c-C₃H₅ 626 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH CH c-C₃H₅ 627 CH₂CH₃ (R)CH₃ H H CH₃ CH CH c-C₃H₅ 628 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH CH c-C₃H₅ 629 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH CH c-C₃H₅ 630 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH CH c-C₃H₅ 631 CH₃ H CH₃ H CH₃ CH CH c-C₃H₅ 632 CH₂CH═CH₂ H CH₃ H CH₃ CH CH c-C₃H₅ 633 CH₂-c-C₃H₅ H CH₃ H CH₃ CH CH c-C₃H₅ 634 CH₂CH₂CH₃ H CH₃ H CH₃ CH CH c-C₃H₅ 635 CH₃ CH₃ H CH₃ CH₃ CH CH c-C₃H₅ 636 CH₂CH═CH₂ CH₃ H CH₃ CH₃ CH CH c-C₃H₅ 637 CH₂-c-C₃H₅ CH₃ H CH₃ CH₃ CH CH c-C₃H₅ 638 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ CH CH c-C₃H₅ 639 CH₃ CH₃ CH₃ H CH₃ CH CH c-C₃H₅ 640 CH₂CH═CH₂ CH₃ CH₃ H CH₃ CH CH c-C₃H₅ 641 CH₂-c-C₃H₅ CH₃ CH₃ H CH₃ CH CH c-C₃H₅ 642 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ CH CH c-C₃H₅ 643 (s)(CH₂)₃ H H CH₃ CH CH c-C₃H₅ 644 (s)(CH₂)₄ H H CH₃ CH CH c-C₃H₅ 645 rac(CH₂)₃ H H CH₃ CH CH c-C₃H₅ 646 rac(CH₂)₄ H H CH₃ CH CH c-C₃H₅ 647 (R)(CH₂)₃ H H CH₃ CH CH c-C₃H₅ 648 (R)(CH₂)₄ H H CH₃ CH CH c-C₃H₅ 649 CH₂CH═CH₂ H H H CH₃ CH C—Cl c-C₃H₅ 650 CH₂-c-C₃H₅ H H H CH₃ CH C—Cl c-C₃H₅ 651 CH₂CH₂CH₃ H H H CH₃ CH C—Cl c-C₃H₅ 652 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 653 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 654 CH₂CH₃ (s)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 655 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 656 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH C—Cl c-C₃H₅ 657 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ CH C—Cl c-C₃H₅ 658 CH₂CH₃ rac-CH₃ H H CH₃ CH C—Cl c-C₃H₅ 659 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH C—Cl c-C₃H₅ 660 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 661 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 662 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 663 CH₂CH₃ (R)CH₃ H H CH₃ CH C—Cl c-C₃H₅ 664 CH₂CH═CH₂ H H H CH₃ CH C—CH₃ c-C₃H₅ 665 CH₂-c-C₃H₅ H H H CH₃ CH C—CH₃ c-C₃H₅ 666 CH₂CH₂CH₃ H H H CH₃ CH C—CH₃ c-C₃H₅ 667 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 668 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 669 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 670 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 671 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 672 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 673 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 674 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 675 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH C—CH₃ c-C₃H₅ 676 CH₂CH═CH₂ H H H CH₃ C—Cl CH c-C₃H₅ 677 CH₂-c-C₃H₅ H H H CH₃ C—Cl CH c-C₃H₅ 678 CH₂CH₂CH₃ H H H CH₃ C—Cl CH c-C₃H₅ 679 CH₂CH═CH₂ (s)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 680 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 681 CH₂CH₃ (s)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 682 CH₂CH₂CH₃ (s)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 683 CH₂CH═CH₂ rac-CH₃ H H CH₃ C—Cl CH c-C₃H₅ 684 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ C—Cl CH c-C₃H₅ 685 CH₂CH₂CH₃ rac-CH₃ H H CH₃ C—Cl CH c-C₃H₅ 686 CH₂CH═CH₂ (R)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 687 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 688 CH₂CH₃ (R)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 689 CH₂CH₂CH₃ (R)CH₃ H H CH₃ C—Cl CH c-C₃H₅ 690 CH₂CH═CH₂ H H H CH₃ C—CH₃ CH c-C₃H₅ 691 CH₂-c-C₃H₅ H H H CH₃ C—CH₃ CH c-C₃H₅ 692 CH₂CH₂CH₃ H H H CH₃ C—CH₃ CH c-C₃H₅ 693 CH₂CH═CH₂ (s)CH₃ H H CH₃ C—CH₃ CH c-C₃H₅ 694 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ C—CH₃ CH c-C₃H₅ 695 CH₂CH₂CH₃ (s)CH₃ H H CH₃ C—CH₃ CH c-C₃H₅ 696 CH₂CH═CH₂ rac-CH₃ H H CH₃ C—CH₃ CH c-C₃H₅ 697 CH₂-c-C₃H₅ rac-CH₃ H H CH₃ C—CH₃ CH c-C₃H₅ 698 CH₂CH₂CH₃ rac-CH₃ H H CH₃ C—CH₃ CH c-C₃H₅ 699 CH₃ H H H CH₃ CH CH C₂H₅ 700 CH₂CH═CH₂ H H H CH₃ CH CH C₂H₅ 701 CH₂-c-C₃H₅ H H H CH₃ CH CH C₂H₅ 702 CH₂CH₂CH₃ H H H CH₃ CH CH C₂H₅ 703 CH₃ (s)CH₃ H H CH₃ CH CH C₂H₅ 704 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH CH C₂H₅ 705 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH CH C₂H₅ 706 CH₂CH₃ (s)CH₃ H H CH₃ CH CH C₂H₅ 707 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH CH C₂H₅ 708 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH CH C₂H₅ 709 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH CH C₂H₅ 710 CH₃ (R)CH₃ H H CH₃ CH CH C₂H₅ 711 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH CH C₂H₅ 712 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH CH C₂H₅ 713 CH₂CH═CH₂ H CH₃ H CH₃ CH CH C₂H₅ 714 CH₂CH₂CH₃ H CH₃ H CH₃ CH CH C₂H₅ 715 CH₂CH═CH₂ CH₃ H CH₃ CH₃ CH CH C₂H₅ 716 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ CH CH C₂H₅ 717 CH₂CH═CH₂ CH₃ CH₃ H CH₃ CH CH C₂H₅ 718 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ CH CH C₂H₅ 719 (s)(CH₂)₃ H H CH₃ CH CH C₂H₅ 720 (s)(CH₂)₄ H H CH₃ CH CH C₂H₅ 721 rac(CH₂)₃ H H CH₃ CH CH C₂H₅ 722 rac(CH₂)₄ H H CH₃ CH CH C₂H₅ 723 H H H H CH₃ CH CH CH═CH₂ 724 CH₃ H H H CH₃ CH CH CH═CH₂ 725 CH₂CH₃ H H H CH₃ CH CH CH═CH₂ 726 CH₂CH═CH₂ H H H CH₃ CH CH CH═CH₂ 727 CH₂-c-C₃H₅ H H H CH₃ CH CH CH═CH₂ 728 CH₂CH₂CH₃ H H H CH₃ CH CH CH═CH₂ 729 H (s)CH₃ H H CH₃ CH CH CH═CH₂ 730 CH₃ (s)CH₃ H H CH₃ CH CH CH═CH₂ 731 CH₂CH₃ (s)CH₃ H H CH₃ CH CH CH═CH₂ 732 CH₂CH═CH₂ (s)CH₃ H H CH₃ CH CH CH═CH₂ 733 CH₂-c-C₃H₅ (s)CH₃ H H CH₃ CH CH CH═CH₂ 734 CH₂CH₂CH₃ (s)CH₃ H H CH₃ CH CH CH═CH₂ 735 CH₂CH═CH₂ rac-CH₃ H H CH₃ CH CH CH═CH₂ 736 CH₂CH₂CH₃ rac-CH₃ H H CH₃ CH CH CH═CH₂ 737 CH₂CH₃ (s)CH₃ H H CH₃ CH CH CH═CH₂ 738 CH₂CH═CH₂ (R)CH₃ H H CH₃ CH CH CH═CH₂ 739 CH₂-c-C₃H₅ (R)CH₃ H H CH₃ CH CH CH═CH₂ 740 CH₂CH₂CH₃ (R)CH₃ H H CH₃ CH CH CH═CH₂ 741 CH₂CH═CH₂ H CH₃ H CH₃ CH CH CH═CH₂ 742 CH₂CH₂CH₃ H CH₃ H CH₃ CH CH CH═CH₂ 743 CH₂CH═CH₂ CH₃ H CH₃ CH₃ CH CH CH═CH₂ 744 CH₂CH₂CH₃ CH₃ H CH₃ CH₃ CH CH CH═CH₂ 745 CH₂CH═CH₂ CH₃ CH₃ H CH₃ CH CH CH═CH₂ 746 CH₂CH₂CH₃ CH₃ CH₃ H CH₃ CH CH CH═CH₂ 747 (CH₂)₃ H H CH₃ CH CH CH═CH₂ 748 (CH₂)₄ H H CH₃ CH CH CH═CH₂ rac: racemate; (S): S configuration; (R) R configuration.

Other examples of compounds according to the invention are the compounds of the general formulae Ia.3, Ib, Ic, Id, Ie and If:

in which R¹, R^(2a), R^(2c), R³, X, Y and R^(b) have the meanings specified in one line in Table 1.

Among the compounds of the general formula I, preference is also given to the compounds of the general formula Ig

in which n, k, R¹, R², R^(a), R^(b), A¹, A², A³, X and Y have the meanings given for formula Ia.

Among the compounds of the general formula I, preference is also given to the compounds of the general formula Ih

in which n, k, R¹, R², R^(a), R^(b), A¹, A², A³, X and Y have the meanings given for formula Ia.

Among the compounds of general formulae Ig and Ih, preference is given to the compounds of general formula Ig.1, Ig.2, Ih.1 and Ih.2

in which n, q, q′, X, Y, R¹, R², R^(a) and R^(b) have the meanings mentioned previously for formulae Ia.1 and Ia.2 and R is CH₂ (compounds Ig.1 and Ig.2) or O (compounds Ih.1 or Ih.2).

Examples of compounds of the formula Ig.1 and Ih.1 are the compounds of the following general formulae Ig.1a, Ig.1b, Ig.1c, Ig.1d, Ig.1e, Ig.1f, Ig.1g, Ig.1h, Ig.1k, Ih.1a, Ih.1b, Ih.1c, Ih.1h, Ih.1e, Ih.1f, Ih.1g, Ih.1h and Ih.1k:

in which R¹, R^(2a), R^(2b), R^(2c), X, Y and R^(b) have the meanings specified in one of the lines 1 to 474 in Table 1.

Examples of compounds of the formula Ig.1 and Ih.1 are the compounds of the following general formulae Ig.2a, Ig.2b, Ig.2c, Ig.2d, Ig.2e, Ih.2a, Ih.2b, Ih.2c, Ih.2d and Ih.2e:

in which R¹, R^(2a), R^(2b), R^(2c), X, Y and R^(b) have the meanings specified in one of the lines 1 to 474 in Table 1.

The compounds I according to the invention are prepared in analogy with methods known from the literature. An important approach to the compounds according to the invention with R being O or N—R³ is offered by the reaction of a hetarylcompound II with an arylsulfonic acid derivative III as depicted in scheme 1.

In scheme 1, n, R¹, R², R³, Ar and Q have the previously mentioned meanings. R is O or N—R³. X is a nucleophilically displaceable leaving group, in particular a halogen atom and, especially, chlorine or bromine. The reaction depicted in scheme 1 takes place under the reaction conditions which are customary for preparing arylsulfonamide compounds or arylsulfonic esters, respectively, and which are described, for example, in J. March, Advanced Organic Chemistry, 3^(rd) edition, John Wiley & Sons, New York, 1985 p 444 and the literature cited therein, European J. Org. Chem. 2002 (13), pp. 2094-2108, Tetrahedron 2001, 57 (27) pp. 5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000, 10(8), pp. 835-838 and Synthesis 2000 (1), pp. 103-108.

The reaction customarily takes place in an inert solvent, for example in an ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, a halohydrocarbon, such as dichloromethane, an aliphatic or cycloaliphatic hydrocarbon, such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumene and the like, or in a mixture of the abovementioned solvents.

The reaction of II with III is customarily carried out in the presence of an auxiliary base. Suitable bases are inorganic bases, such as sodiumcarbonate or potassiumcarbonate, or sodiumhydrogencarbonate or potassiumhydrogencarbonate, and organic bases, for example trialkylamines, such as triethylamine, or pyridine compounds, such as pyridine, lutidine and the like. The latter compounds can at the same time serve as solvents. The auxiliary base is customarily employed in at least equimolar quantities, based on the amine compound II.

The compounds of the general formula II are known per se or, in case R is N—R^(3a), can be prepared in the manner shown in schemes 2.

In scheme 2, n, R² and Q have the previously mentioned meanings. R^(1′) has the meanings different from hydrogen which are specified for R¹ or is a suitable protecting group. Suitable protecting groups are disclosed, for example, in P. Kocienski, Protecting Groups, Thieme-Verlag, Stuttgart 2000, Chapter 6. Y is a nucleophilically displaceable leaving group, in particular a halogen atom, e.g. chlorine or bromine, or an alkylsulfonyl group, e.g. methylsulfonyl.

The reaction depicted in step a) in scheme 2 takes place under the reaction conditions which are customary for a nucleophilic substitution on an aromatic radical and which are described, for example, in Tetrahedron 1999, 55(33), pp. 1024.3-10252, J. Med. Chem. 1997, 40(22), pp. 3679-3686 and Synthetic Communications, 1993, 23(5), pp. 591-599. Where appropriate, it can be advantageous to convert a ring nitrogen atom in the Q group into its N-oxide (see, for example, Angew. Chem. Int. Ed. Engl., 2002 41(11), pp. 1937-1940, J. Med. Chem. 1985, 28(2), pp. 248-252 and Tetrahedron Lett. 2002 43(17) pp. 3121-3123). This approach has proved to be of value, in particular, for preparing compounds I in which Q is a pyridin-2,4-diyl group. In connection with the subsequent reduction of the nitro group in VI (step b), the N-oxide group is also reduced. For this, the reduction is carried out, for example, in the presence of indium salts.

If 5-bromonitropyridine is used as compound V in step a) in accordance with scheme 2, the coupling is also achieved under palladium catalysis in the presence of an auxiliary base, for example an alkali metal carbonate such as cesium carbonate. Particularly suitable palladium catalysts in this connection are palladium(0) compounds or palladium compounds which are able to form a palladium(0) compound under reaction conditions, e.g. palladium dichloride, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), advantageously in combination with phosphine ligands, e.g. triaryiphosphines, such as triphenylphosphine, trialkylphosphines, such as tributylphosphine, and cycloalkylphosphines, such as tricyclohexylphosphine, and, especially, using phosphine chelate ligands, such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. The conditions which are required for reactions of this nature are described, for example, in Tetrahedron Lett. 2001, 42(22), p. 3681 and Tetrahedron Lett. 2002, 43(12), pp. 2171-2173.

In step b), the nitro group in VI is reduced to the NH₂ group in II. Subsequently, in step c), the NH₂ group can be converted into a —NR^(3′)H group, in which R^(3′) has the meanings different from hydrogen which are specified for R³.

The reaction conditions which are required for step b) correspond to the customary conditions for reducing aromatic nitro groups which have been described extensively in the literature (see, for example, J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, New-York, 1985, p. 1183 and the literature cited in this reference).

The reduction is achieved, for example, by reacting the nitro compound VII with a metal such as iron, zinc or tin under acidic reaction conditions, i.e. using nascent hydrogen, or using a complex hydride such as lithium aluminum hydride or sodium borohydride, preferably in the presence of transition metal compounds of nickel or cobalt such as NiCl₂(P(phenyl)₃)₂, or CoCl₂, (see Ono et al. Chem. Ind. (London), 1983 p. 480), or using NaBH₂S₃ (see Lalancette et al. Can. J. Chem. 49, 1971, p. 2990), with it being possible to carry out these reductions, depending on the given reagent, in substance or in a solvent or diluent. Alternatively, the reduction of VI to II can be carried out with hydrogen in the presence of a transition metal catalyst, e.g. using hydrogen in the presence of catalysts based on platinum, palladium, nickel, ruthenium or rhodium. The catalysts can contain the transition metal in elemental form or in the form of a complex compound, of a salt or of an oxide of the transition metal, with it being possible, for the purpose of modifying the activity, to use customary coligands, e.g. organic phosphine compounds, such as triphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphines or phosphites. The catalyst is customarily employed in quantities of from 0.001 to 1 mol per mol of compound VI, calculated as catalyst metal. In a preferred variant, the reduction is effected using tin(II) chloride in analogy with the methods described in Bioorganic and Medicinal Chemistry Letters; 2002, 12(15), pp. 1917-1919 and J. Med. Chem. 2002, 45(21), pp. 4679-4688. The reaction of VI with tin(II) chloride is preferably carried out in an inert organic solvent, preferably an alcohol such as methanol, ethanol, isopropanol or butanol.

Reducing VI results in compounds II in which R³ is hydrogen. Customary methods can then be used to react these compounds with an alkylating agent R^(3′)—X, in which R^(3′) is C₁-C₄-alkyl and X is a nucleophilically displaceable leaving group (e.g. halogen, such as chlorine, bromine or iodine), resulting in a compound II in which R³=alkyl (step c). The reaction conditions which are required for this are disclosed, for example, in WO 02/83652, Tetrahedron 2000, 56(38) pp. 7553-7560 and Synlett. 2000 (4), pp. 475-480.

The compound I can also be prepared by the route depicted in scheme 3:

In scheme 3, n, R, R¹, R², Ar and Q have the previously mentioned meanings. Y is a nucleophilically displaceable leaving group, in particular a halogen atom, e.g. chlorine or bromine, or an alkylsulfonyl group, e.g. methylsulfonyl. The reaction of VII with VIII, as depicted in scheme 3, takes place under the reaction conditions specified for scheme 2, step a). Compounds of the general formulae VII and VIII are known or can be prepared in analogy with the methods known from the literature. Compounds or the formula VIII, wherein R is N—R³ or an oxygen atom can be prepared by amidation of the corresponding aminocompound X-Q-NHR³ (or esterification of the corresponding hydroxycompound X-Q-OH) with a sulfonylhalide, especially with a sulfonylchloride of the formula Z—SO₂—Ar, wherein Z is halogen, especially chlorine or bromine, according to standard methods of organic chemistry (see e.g. J. March, Advanced Organic Chemistry, 3^(rd) edition, John Wiley & Sons, New York, 1985 p 444 and the literature cited therein).

Compounds of general formula I, in which R¹ is an allyl group, can be converted into compounds possessing different R¹ substituents using the synthetic route shown in scheme 4.

In scheme 4, n, R, R², Ar and Q have the previously mentioned meanings. The elimination of the allyl group, as depicted in step a) in scheme 4, is achieved, for example, by reacting I [R¹=allyl] with an allyl trapping agent, such as mercaptobenzoic acid or 1,3-dimethylbarbituric acid, in the presence of catalytic quantities of palladium (0) compounds or palladium compounds which are able to form a palladium(0) compound under reaction conditions, e.g. palladium dichloride, tetrakis(triphenylphosphine)-palladium(0) or tris(dibenzylideneacetone)dipalladium(0), advantageously in combination with phosphine ligands, e.g. triaryiphosphines, such as triphenylphosphine, trialkyiphosphines, such as tributylphosphine, and cycloalkylphosphines, such as tricyclohexylphosphine, and especially with phosphine chelate ligands, such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or 1,4-bis(diphenylphosphino)butane, using methods known from the literature (with regard to eliminating N-allyl in the presence of mercaptobenzoic acid, see WO 94/24088; with regard to eliminating in the presence of 1,3-dimethylbarbituric acid, see J. Am. Chem. Soc. 2001, 123 (28), pp. 6801-6808 and J. Org. Chem 2002, 67(11) pp. 3718-3723). Alternatively, the elimination of N-allyl, as depicted in scheme 4 step a), can also be effected by reacting in the presence of rhodium compounds, such as tris(triphenylphosphine)chlororhodium(I), using methods known from the literature (see J. Chem. Soc., Perkin Transaction I: Organic and Bio-Organic Chemistry 1999 (21) pp. 3089-3104 and Tetrahedron Asymmetry 1997, 8(20), pp. 3387-3391).

The resulting piperazine compound I [R¹═H] can then be reacted, in a known manner, in the sense of an alkylation, with a compound R¹—X. In this compound, R¹ is C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl or C₃-C₆-cycloalkyl-C₁-C₄-alkyl and X is a nucleophilically displaceable leaving group, e.g. halogen, trifluoroacetate, alkylsulfonate, arylsulfonate, alkyl sulfate and the like. The reaction conditions which are required for the alkylation in step b) have been adequately disclosed, e.g. in Bioorganic and Medicinal Chemistry Lett. 2002, 12(7), pp. 2443-2446 and also 2002, 12(5), pp. 1917-1919.

The conversion, as depicted in scheme 4, step b), of the piperazine compound I [R¹═H] obtained in step a) can also be achieved, in the sense of a reductive amination, by reacting I [R¹═H] with a suitable ketone or aldehyde in the presence of a reducing agent, e.g. in the presence of a borohydride such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The skilled person is familiar with the reaction conditions which are required for a reductive amination, e.g. from Bioorganic and Medicinal Chemistry Lett. 2002, 12(5), pp. 795-798 and 12(7) pp. 1269-1273.

The conversion, as depicted in scheme 4, step b), of the piperazine compound I [R¹═H] obtained in step a) can also be achieved by successive acylation and subsequent reduction of the acylation product, using the method depicted in scheme 4a:

In scheme 4a, n, R, R², Ar and Q have the previously mentioned meanings. The acylation in step a) and the reduction in step b) are effected using standard methods of organic chemistry as are described, for example, in J. March, Advanced Organic Chemistry, 3rd ed. J. Wiley & Sons, New York 1985, p. 370 and 373 (acylation) and p. 1099 f. and in the literature cited in this publication (with regard to acylation, see also Synth. Commun. 1986, 16, p. 267, and with regard to reduction, see also J. Heterocycl. Chem. 1979, 16, p. 1525).

In compounds of the general formula I which carry a halogen atom, in particular bromine or iodine, on the aromatic radical Ar, the halogen atom can be converted into an alkyl, alkenyl, cycloalkyl, alkynyl or cycloalkylalkyl group using methods which are known per se. The conversion is achieved by coupling the halo compound I to an alkyl-, alkenyl-, alkynyl-, cycloalkyl- or cycloalkylalkyl-boronic acid compound under the conditions of a Suzuki coupling as is described, for example, in Tetrahedron Lett. 2002, 43, pp. 6987-6990; Chem. Rev. 1995, 95, pp. 2457-2483 and J. Org. Chem. 66(21) (2001), pp. 7124-7128.

Compounds of the formula I, wherein R is CR^(3a)R^(3b), can be also prepared by the synthetic route illustrated in scheme 5:

In scheme 5, n, R¹, R², Q, R^(3a), R^(3b) and Ar are as defined above. L is a nucleophilically displaceable leaving group, in particular a halogen atom such as chlorine or bromine or a sulfonate group, e.g. a C₁-C₄-alkylsulfonate such as methanesulfonate or an arylsulfonate such benzenesulfoante or tosylate (toluene sulfonate). L may also be OH, when R^(3a), R^(3b) are different from hydrogen. The reaction depicted in the first step of scheme 5 takes place under the reaction conditions which are customary for preparing arylsulfide compounds which are described, for example, in J. March, Advanced Organic Chemistry, 3^(rd) edition, John Wiley & Sons, New York, 1985 p 360 to 362, and in the literature cited therein.

In the second step of scheme 5 the sulfide X obtained in the first step is oxidized to the corresponding sulfone I (R═CR^(3a)R^(3b)) under reaction conditions which are customary for preparing arylsulfone compounds from the corresponding arylsulfides and which are described, for example, in J. March, Advanced Organic Chemistry, 3^(rd) edition, John Wiley & Sons, New York, 1985 p 1089 f. and in the literature cited therein.

The compounds of the formula IX are known in the art or can be prepared according to the method depicted in scheme 6:

In scheme 6, n, R¹, R², Q, R^(3a), R^(3b) and Ar are as defined above. Hal is halogen, especially chlorine, bromine or iodine. In step (a) of scheme 6 the halogen compound XI is first metallized, i.e. converted into the corresponding lithium compound or magnesium compound by standard methods of organic chemistry and the thus obtained metal compound is reacted with an aldehyde or ketone to obtain the alcohol XII (see e.g. Tetrahedron 2003, 59 (24), 4303-4308). In step (b) he OH group of XII is then converted into a suitable leaving group, e.g. into a halogen atom by reaction with thionylhalide such as SOCl₂ or phosphorylhalide such as POCl₃, or into an alkylsulfonate or arylsulfonate by reaction with an alkylsulfonylhalide such as methanesulfonylchloride or with an arylsulfonylhalide such as toluoenesulfonylchloride (see e.g. J. Med. Chem. 1985, 28 (12), 1790-1796).

Alternatively the halogen compound XI is converted into the carbonyl compound XIII (step c, see e.g. J. Med. Chem. 1987, 30 (8), 1494-1497), which is then reduced (R^(3b)═H) or reacted with an alkylgrignard R^(3b)—Mg—X (X=halogen, e.g. Cl or Br) to obtain the alcohol XII (step (d), see e.g. J. Org. Chem. 2003, 68 (9), 3736-3738).

If not otherwise indicated, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH 2002.

Examples of solvents which can be used are ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, aprotic polar solvent, such as dimethylformamide, dimethyl sulfoxide, dimethoxyethane, and acetonitrile, aromatic hydrocarbons, such as toluene and xylene, ketones, such as acetone or methyl ethyl ketone, halohydrocarbons, such as dichloromethane, trichloromethane and dichloroethane, esters, such as ethyl acetate and methyl butyrate, carboxylic acids, such as acetic acid or propionic acid, and alcohols, such as methanol, ethanol, n-propanol, isopropanol and butanol.

If desired, it is possible for a base to be present in order to neutralize protons which are released in the reactions. Suitable bases include inorganic bases, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, and, in addition, alkoxides, such as sodium methoxide or sodium ethoxide, alkali metal hydrides, such as sodium hydride, and also organometallic compounds, such as butyllithium compounds or alkylmagnesium compounds, or organic nitrogen bases, such as triethylamine or pyridine. The latter compounds can at the same time serve as solvents.

The crude product is isolated in a customary manner, for example by filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by means of recrystallizing from a solvent, by means of chromatography or by means of converting into an acid addition salt.

The acid addition salts are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

The compounds according to the invention of the formula I are highly selective dopamine D₃ receptor ligands which, because of their low affinity for other receptors such as D₁ receptors, D₄ receptors, α1-adrenergic and/or α2-adrenergic receptors, muscarinergic receptors, histamine receptors, opiate receptors and, in particular, dopamine D₂ receptors, give rise to fewer side-effects than do the classic neuroleptics, which are D₂ receptor antagonists.

The high affinity of the compounds according to the invention for D₃ receptors is reflected in very low in-vitro K_(i) values of as a rule less than 100 nM (nmol/l), in particular less than 50 nM and, in particular, of less than 10 nM. The displacement of [¹²⁵I]-iodosulpride can, for example, be used in receptor binding studies for determining binding affinities for D₃ receptors.

The selectivity K_(i)(D₂)/K_(i)(D₃) of the compounds according to the invention is as a rule at least 10, preferably at least 30, even better at least 50 and particularly advantageously at least 100. The displacement of [³H]SCH23390, [¹²⁵I] iodosulpride or [¹²⁵I] spiperone can be used, for example, for carrying out receptor binding studies on D₁, D₂ and D₄ receptors.

Because of their binding profile, the compounds can be used for treating diseases which respond to dopamine D₃ ligands, i.e. they are effective for treating those disturbances or diseases in which exerting an influence on (modulating) the dopamine D₃ receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of these diseases are disturbances or diseases of the central nervous system.

Disturbances or diseases of the central nervous system are understood as meaning disturbances which affect the spinal chord and, in particular, the brain. Within the meaning of the invention, the term “disturbance” denotes anomalies which are as a rule regarded as being pathological conditions or functions and which can manifest themselves in the form of particular signs, symptoms and/or malfunctions. While the treatment according to the invention can be directed toward individual disturbances, i.e. anomalies or pathological conditions, it is also possible for several anomalies, which may be causatively linked to each other, to be combined into patterns, i.e. syndromes, which can be treated in accordance with the invention.

The disturbances which can be treated in accordance with the invention are, in particular, psychiatric and neurological disturbances. These disturbances include, in particular, organic disturbances, including symptomatic disturbances, such as psychoses of the acute exogenous reaction type or attendant psychoses of organic or exogenous cause, e.g., in association with metabolic disturbances, infections and endocrinopathogies; endogenous psychoses, such as schizophrenia and schizotype and delusional disturbances; affective disturbances, such as depressions, mania and/or manicdepressive conditions; and also mixed forms of the above-described disturbances; neurotic and somatoform disturbances and also disturbances in association with stress; dissociative disturbances, e.g. loss of consciousness, clouding of consciousness, double consciousness and personality disturbances; disturbances in attention and waking/sleeping behavior, such as behavioral disturbances and emotional disturbances whose onset lies in childhood and youth, e.g. hyperactivity in children, intellectual deficits, in particular attention disturbances (attention deficit disorders), memory disturbances and cognitive disturbances, e.g. impaired learning and memory (impaired cognitive function), dementia, narcolepsy and sleep disturbances, e.g. restless legs syndrome; development disturbances; anxiety states, delirium; sexlife disturbances, e.g. impotence in men; eating disturbances, e.g. anorexia or bulimia; addiction; and other unspecified psychiatric disturbances.

The disturbances which can be treated in accordance with the invention also include Parkinson's disease and epilepsy and, in particular, the affective disturbances connected thereto.

The addiction diseases include psychic disturbances and behavioral disturbances which are caused by the abuse of psychotropic substances, such as pharmaceuticals or narcotics, and also other addiction diseases, such as addiction to gaming (impulse control disorders not elsewhere classified). Examples of addictive substances are: opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics and tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate and other stimulants including caffeine. Addictive substances which come particularly into consideration are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

With regard to the treatment of addiction diseases, particular preference is given to those compounds according to the invention of the formula I which themselves do not possess any psychotropic effect. This can also be observed in a test using rats, which, after having been administered compounds which can be used in accordance with the invention, reduce their self administration of psychotropic substances, for example cocaine.

According to another aspect of the present invention, the compounds according to the invention are suitable for treating disturbances whose causes can at least partially be attributed to an anomalous activity of dopamine D₃ receptors.

According to another aspect of the present invention, the treatment is directed, in particular, toward those disturbances which can be influenced, within the sense of an expedient medicinal treatment, by the binding of preferably exogeneously administered binding partners (ligands) to dopamine D₃ receptors.

The diseases which can be treated with the compounds according to the invention are frequently characterized by progressive development, i.e. the above-described conditions change over the course of time; as a rule, the severity increases and conditions may possibly merge into each other or other conditions may appear in addition to those which already exist.

The compounds according to the invention can be used to treat a large number of signs, symptoms and/or malfunctions which are connected with the disturbances of the central nervous system and, in particular, the abovementioned conditions. These signs, symptoms and/or malfunctions include, for example, a disturbed relationship to reality, lack of insight and ability to meet customary social norms or the demands made by life, changes in temperament, changes in individual drives, such as hunger, sleep, thirst, etc., and in mood, disturbances in the ability to observe and combine, changes in personality, in particular emotional lability, hallucinations, ego-disturbances, distractedness, ambivalence, autism, depersonalization and false perceptions, delusional ideas, chanting speech, lack of synkinesia, short-step gait, flexed posture of trunk and limbs, tremor, poverty of facial expression, monotonous speech, depressions, apathy, impeded spontaneity and decisiveness, impoverished association ability, anxiety, nervous agitation, stammering, social phobia, panic disturbances, withdrawal symptoms in association with dependency, maniform syndromes, states of excitation and confusion, dysphoria, dyskinetic syndromes and tic disturbances, e.g. Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigo syndromes, e.g. peripheral positional, rotational and oscillatory vertigo, melancholia, hysteria, hypochondria and the like.

Within the meaning of the invention, a treatment also includes a preventive treatment (prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term treatment, for example within the context of a maintenance therapy.

The compounds according to the invention are preferentially suitable for treating diseases of the central nervous system, in particular for treating affective disturbances; neurotic disturbances, stress disturbances and somatoform disturbances and psychoses, and, in particular, for treating schizophrenia and depression. Because of their high selectivity with regard to the D₃ receptor, the compounds I according to the invention are also suitable for treating disturbances of kidney function, in particular disturbances of kidney function which are caused by diabetes mellitus (see WO 00/67847) and, especially, diabetic nephropathy.

Within the context of the treatment, the use according to the invention of the described compounds involves a method. In this method, an effective quantity of one or more compounds, as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other active compounds or active compound-containing preparations such that a daily dose of preferably from about 0.1 to 1000 mg/kg of bodyweight, in the case of oral administration, or of from about 0.1 to 100 mg/kg of bodyweight, in the case of parenteral administration, is supplied to an individual to be treated.

The invention also relates to the production of pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being, productive animal or domestic animal. Thus, the ligands are customarily administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient together with at least one ligand according to the invention and, where appropriate, other active compounds. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres. When producing the compositions, inhibitors according to the invention are usually mixed or diluted with an excipient. Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.

Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4^(th) edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to explain the invention without limiting it.

The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (δ) expressed in parts per million (ppm). The relative area of the shifts in the ¹H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).

PREPARATION EXAMPLES Example 1 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide 1.1 1-Allyl-4-(5-nitropyridin-2-yl)piperazine

2.0 g (12.61 mmol) of 2-chloro-5-nitropyridine were dissolved in 8 ml of dimethylformamide, and 3.49 g (25.23 mmol) of potassium carbonate were added. After that, a solution of 1.75 g (13.88 mmol) of N-allylpiperazine in 2 ml of dimethylformamide was added slowly dropwise to the reaction mixture (exothermic reaction). The reaction mixture was then stirred at room temperature for 2 hours. After the solvent had been concentrated down to dryness, the resulting residue was stirred up in 100 ml of heptane. The precipitate which remained was filtered off with suction. The filtrate was concentrated, resulting in 720 mg of the title compound. The precipitate which had been filtered off with suction was treated with 150 ml of water and extracted three times with diethyl ether. The organic phase was washed with a saturated solution of sodium chloride and dried over sodium sulfate. A further 2.24 g of the title compound were isolated after the solvent had been filtered and concentrated down to dryness. The total yield of 1-allyl-4-(5-nitropyridin-2-yl)piperazine was 2.96 g (95% of theory).

MS [m+1]: 249.

1.2 6-(4-Allylpiperazin-1-yl)pyridine-3-amine

2.2 g (8.86 mmol) of 1-allyl-4-(5-nitropyridin-2-yl)piperazine from Example 1.1 were dissolved in 150 ml of methanol after which 18 g (79.75 mmol) of tin(II) chloride dihydrate were added and the mixture was stirred at 70° C. for 4 hours. After the solvent had been evaporated down to dryness, water was added to the residue. The aqueous reaction mixture was made alkaline with dilute sodium hydroxide solution and then extracted with ethyl acetate. The solid which had precipitated out was filtered off. After that, the phases were separated and the aqueous phase was extracted in each case twice with ethyl acetate and dichloromethane. The combined organic phases were dried over sodium sulfate. 1.74 g (90% of theory) of the title compound were obtained after the drying agent had been removed and the solvent had been evaporated down to dryness.

MS [m+1]: 219.

1.3 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide

1.4 g (7.97 mmol) of 6-(4-allylpiperazin-1-yl)pyridin-3-ylamine from Example 1.2 and 1.74 g (7.97 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 30 ml of tetrahydrofuran at room temperature. 3.3 ml (23.91 mmol) of triethylamine were then added to this mixture. After that, the reaction mixture was stirred overnight at room temperature. After the solvent had been evaporated to dryness, water was added to the residue. The aqueous reaction mixture was made acid with 1N hydrochloric acid and extracted twice with diethyl ether. After that, the aqueous phase was made alkaline (pH 9-10) with a 1N aqueous solution of sodium hydroxide and then extracted twice with diethyl ether. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the resulting residue was chromatographed on silica gel using cyclohexane/ethyl acetate (45:55% to 100% ethyl acetate). The filtrate was evaporated down to dryness. The resulting residue was thoroughly stirred in 10 ml of heptane, filtered off in suction and dried, with 1.93 g (61% of theory) of the title compound being obtained.

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 7.7 (s, 1H); 7.6 (d, 2H); 7.4 (d, 1H); 7.3 (d, 2H); 6.6 (d, 1H); 6.4 (bs, 1H); 5.9 (m, 1H); 5.2 (m, 2H); 3.5 (m, 4H); 3.1 (m, 2H); 3.0 (m, 1H); 2.5 (m, 4H); 1.2 (d, 6H).

MS [m+1]: 401.

Example 2 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-propylbenzenesulfonamide

373 mg of the title compound were obtained in an analogous manner to that described in Example 1.3 when starting with 4-n-propylbenzenesulfonyl chloride.

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 7.7 (m, 1H); 7.6 (m, 2H); 7.4 (d, 1H); 7.3 (m, 2H); 6.6 (d, 1H); 6.3 (bs, 1H); 5.9 (m, 1H); 5.2 (m, 2H); 3.5 (m, 4H); 3.1 (m, 2H); 2.6 (m, 2H); 2.5 (m, 4H); 1.7 (m, 2H); 0.9 (m, 3H).

MS [m+1]: 401.

Example 3 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-butylbenzenesulfonamide

405 mg of the title compound were obtained in an analogous manner to that described in Example 1.3 when starting with 4-n-butylbenzenesulfonyl chloride.

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 7.7 (m, 1H); 7.6 (m, 2H); 7.4 (d, 1H); 7.3 (m, 2H); 6.6 (d, 1H); 6.2 (bs, 1H); 5.9 (m, 1H); 5.2 (m, 2H); 3.5 (m, 4H); 3.0 (m, 2H); 2.7 (m, 2H); 2.5 (m, 4H); 1.6 (m, 2H); 1.4 (m, 2H); 0.9 (m, 3H).

MS [m+1]: 415.

Example 4 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide

500 mg of the title compound were obtained in an analogous manner to that described in Example 1.3 when starting with 4-trifluoromethylbenzenesulfonyl chloride.

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 7.9 (d, 2H); 7.8 (m, 3H); 7.3 (d, 1H); 6.6 (d, 1H); 5.9 (m, 1H); 5.2 (m, 2H); 3.5 (m, 4H); 3.1 (m, 2H); 2.5 (m, 4H).

MS [m+1]: 427.

Example 5 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-ethylbenzenesulfonamide hydrochloride

The Example 1.3 was repeated with 4-ethylbenzenesulfonyl chloride being used instead of 4-isopropylbenzenesulfonyl chloride. The resulting reaction product was converted into the hydrochloride with ethereal hydrochloric acid, with 480 mg (please complete) of the title compound being obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.5 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 2H); 7.6 (d, 2H); 7.4 (m, 3H); 6.9 (d, 1H); 6.0 (m, 1H); 5.5 (m, 2H); 4.3 (m, 2H); 3.8 (m, 2H); 3.4 (m, 2H); 3.3 (m, 2H); 3.0 (m, 2H); 2.7 (m, 2H); 1.2 (t, 3H).

MS [m+1]: 387 (free base).

Example 6 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-vinylbenzenesulfonamide hydrochloride

Example 1.3 was repeated with 4-vinylbenzenesulfonyl chloride being used instead of 4-isopropylbenzenesulfonyl chloride. The resulting reaction product was converted into the hydrochloride with ethereal hydrochloric acid, with 300 mg of the title compound being obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.1 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (m, 4H); 7.3 (d, 1H); 6.9 (d, 1H); 6.8 (dd, 1H); 6.0 (m, 2H); 5.5 (m, 3H); 4.3 (m, 2H); 3.8 (m, 2H); 3.4 (m, 2H); 3.2 (m, 2H); 3.0 (m, 2H).

MS [m+1]: 385 (free base).

Example 7 4-Isopropyl-N-(6-piperazin-1-ylpyridin-3-yl)benzenesulfonamide

95 mg (0.1 mmol) of tris-(dibenzylideneacetone)dipalladium(0) and 44 mg (0.1 mmol) of 1,4-bis-(diphenylphosphino)butane were dissolved in 10 ml of tetrahydrofuran under an argon atmosphere. A solution composed of 1.1 g (2.75 mmol) of N-[6-(4-allylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide from Example 1.3 I in 3 ml of tetrahydrofuran was then added dropwise to the reaction mixture. After that, a solution of 386 mg (2.5 mmol) of 2-mercaptobenzoic acid in 2 ml of tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 90 minutes. A solution of a further 386 mg (2.5 mmol) of 2-mercaptobenzoic acid in 2 ml of tetrahydrofuran was then added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature and, after that, the solvent was evaporated down to dryness. 150 ml of water were added to the resulting residue, after which the mixture was made acid with 1N aqueous hydrochloric acid and extracted three times with diethyl ether. The aqueous phase was then made alkaline, to pH>11, with a 1N aqueous solution of sodium hydroxide and subsequently extracted three times with dichloromethane. After that, the aqueous phase was adjusted to pH 8-9, saturated with an aqueous solution of sodium chloride and, after that, extracted several times with dichloromethane. 840 mg (82% of theory) of the title compound were obtained after the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness.

¹H-NMR (400 MHz, CDCl₃): δ [ppm] 7.7 (d, 1H); 7.6 (d, 2H); 7.4 (dd, 1H); 7.3 (d, 2H); 6.6 (d, 1H); 3.5 (m, 4H); 3.0 (m, 5H); 1.2 (d, 6H).

MS [m+1]: 361.

Example 8 N-{6-[4-(Cyclohexylmethyl)piperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide hydrochloride

150 mg (0.42 mmol) of 4-isopropyl-N-(6-piperazin-1-yl-pyridin-3-yl)-benzenesulfonamide from Example 7 and 51 mg (0.46 mmol) of cyclohexanealdehyde were dissolved in 5 ml of dichloromethane and 40 μl (0.62 mmol) of glacial acetic acid under a nitrogen atmosphere. 133 mg (0.63 mmol) of sodium trisacetoxyborohydride were then added. The mixture was stirred at room temperature for 90 minutes and, after that, the solvent was evaporated down to dryness. The resulting residue was taken up in water and this mixture was made to pH>11 with a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted with diethyl ether. After the organic phase had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was converted into the hydrochloride with ethereal hydrochloric acid, resulting in 156 mg (76% of theory) of the title compound.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] 10.4 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (d, 1H); 6.9 (d, 1H); 4.2 (m, 2H); 3.5 (m, 2H); 3.4 (m, 2H); 3.0 (m, 5H); 1.8 (m, 3H); 1.7 (m, 3H); 1.2 (m, 9H); 1.0 (m, 2H).

MS [m+1]: 457 (free base).

The compounds of Examples 9 to 12 were prepared in an analogous manner.

Example 9 N-[6-(4-Isobutylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] 10.4 (bs, 1H); 10.0 (s, 1H); 7.8 (m, 1H); 7.6 (d, 2H); 7.5 (d, 2H); 7.4 (m, 1H); 6.9 (d, 1H); 4.2 (d, 2H); 3.5 (d, 2H); 3.4 (m, 2H); 3.0 (m, 5H); 2.1 (m, 1H); 1.2 (d, 6H); 1.0 (d, 6H).

MS [m+1]: 417 (free base).

Example 10 4-Isopropyl-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]benzenesulfonamide

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 7.7 (d, 1H); 7.6 (d, 2H); 7.4 (dd, 1H); 7.3 (d, 2H); 6.6 (d, 1H); 3.5 (m, 4H); 3.0 (m, 1H); 2.5 (m, 4H); 2.3 (s, 3H); 1.2 (d, 6H).

MS [m+1]: 375.

Example 11 N-[6-(4-Ethylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] 10.4 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (d, 1H); 6.9 (d, 1H); 4.3 (m, 2H); 3.5 (m, 2H); 3.2 (m, 2H); 3.1 (m, 2H); 3.0 (m, 3H); 1.3 (m, 3H); 1.2 (d, 6H).

MS [m+1]: 389 (free base).

Example 12 N-{6-[4-(Cyclopropylmethyl)piperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide hydrochloride

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] 10.8 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (d, 1H); 6.9 (d, 1H); 4.3 (m, 2H); 3.6 (m, 2H); 3.3 (m, 2H); 3.0 (m, 5H); 1.2 (d, 6H); 1.1 (m, 1H); 0.6 (m, 2H); 0.4 (m, 2H).

MS [m+1]: 415 (free base)

Example 13 N-[6-(4-Allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride 13.1 3-Methyl-1-(5-nitropyridin-2-yl)piperazine

872 mg (6.31 mmol) of potassium carbonate were added to a solution of 500 mg (3.15 mmol) of 2-chloro-5-nitropyridine in 7 ml of dimethylformamide. After that, a solution of 350 mg (3.32 mmol) of 2-methylpiperazine in 3 ml of dimethylformamide was slowly added dropwise to the reaction mixture while cooling with ice (exothermic reaction). The reaction mixture was stirred for 1 hour while cooling with ice and then stirred overnight at room temperature. After the solvent had been evaporated to dryness, the residue was taken up in water and this mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness, with 3-methyl-1-(5-nitropyridin-2-yl)piperazine (Yield: 650 mg, 89% of theory) being obtained.

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 9.0 (s, 1H); 8.2 (d, 1H); 6.6 (d, 1H), 4.4 (m, 2H); 3.2 (m, 1H); 3.1 (m, 1H); 2.9 (m, 2H); 2.7 (m, 1H); 1.2 (m, 3H).

¹³C-NMR (125 MHz, CDCl₃): 160.4 (C); 146.5 (CH); 134.9 (C); 133.0 (C); 104.5 (CH); 52.2 (CH₂); 50.6 (CH); 45.7 (CH₂); 45.4 (CH₂); 19.6 (CH₃).

13.2 1-Allyl-2-methyl-4-(5-nitropyridin-2-yl)piperazine

630 mg (2.72 mmol) of 3-methyl-1-(5-nitropyridin-2-yl)piperazine from Example 13.1 and 267 μl (3.09 mmol) of allyl bromide were dissolved in 10 ml of dimethylformamide. 1.2 ml (8.4 mmol) of triethylamine were then added dropwise to the solution. After the mixture had been stirred at room temperature for 1 hour, a further 65 μl (0.75 mmol) of allyl bromide were added dropwise to the reaction mixture, which was then stirred for a further hour. After that, a further 65 μl (0.75 mmol) of allyl bromide and 0.5 ml (3.6 mmol) of triethylamine were added drop-wise. The mixture was then stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was taken up in water and this solution was made alkaline using a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness, with 707 mg (90% of theory) of the title compound being obtained.

MS [m+1]: 263.

13.3 6-(4-Allyl-3-methylpiperazin-1-yl)pyridine-3-amine

4.975 g (22.05 mmol) of tin(II) chloride dihydrate were added to a solution of 707 mg (2.45 mmol) of 1-allyl-2-methyl-4-(5-nitropyridin-2-yl)piperazine from Example 13.2 in 50 ml of methanol and the resulting mixture was stirred at 70° C. for 90 minutes. After the solvent had been evaporated down to dryness, water was added to the resulting residue and the mixture was made alkaline using a dilute aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction and the phases were separated. The aqueous phase was extracted with dichloromethane. After that, the combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness. The resulting title compound was used in the next step without any further purification.

MS [m+1]: 233.

13.4 N-[6-(4-Allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride

305 mg (1.31 mmol) of 6-(4-allyl-3-methylpiperazin-1-yl)pyridin-3-ylamine from Example 13.3 and 301 mg (1.38 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 10 ml of tetrahydrofuran at room temperature, after which 0.55 ml (3.94 mmol) of triethylamine was added dropwise. After that, the reaction mixture was stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and the mixture was made acid with 1N hydrochloric acid and extracted twice with diethylether. The aqueous phase was made alkaline, to pH 9-10, using a 1N aqueous solution of sodium hydroxide and then extracted twice with diethyl ether. After the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was purified by column chromatography (cyclohexane/ethylacetate from 50:50 to 20:80). After that, the filtrate was evaporated down to dryness. The resulting residue was converted into the hydrochloride using ethereal hydrochloric acid, with 417 mg (74% of theory) of the title compound being obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.3 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (d, 1H); 6.9 (d, 1H); 6.0 (m, 1H); 5.5 (m, 2H); 4.3 (m, 1H); 4.0 (m, 1H); 3.7 (m, 1H); 3.4 (m, 1H); 3.2 (m, 3H); 3.0 (m, 3H); 1.4 (d, 3H); 1.2 (d, 6H).

MS [m+1]: 415 (free base).

Example 13a N-{6-[4-Allyl-(3S)-methylpiperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide (S enantiomer as free base)

The preparation was effected in analogy with the preparation of the racemic compound, with enantiomerically pure (2S)-methylpiperazine being used in step 13.1 instead of racemic 2-methylpiperazine.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.3 (bs, 1H); 10.0 (s, 1H); 7.8 (s, 1H); 7.6 (d, 2H); 7.4 (d, 1H); 7.3 (d, 1H); 6.9 (d, 1H); 6.0 (m, 1H); 5.5 (m, 2H); 4.3 (m, 2H); 4.0 (m, 1H); 3.7 (m, 1H); 3.4 (m, 1H); 3.2 (m, 2H); 3.1 (m, 1H); 3.0 (m, 2H).1.4 (d, 3H); 1.2 (d, 6H).

MS [m+1]: 415 (free base)

Example 14 4-Isopropyl-N-[6-(3-methyl-4-propylpiperazin-1-yl)pyridin-3-yl]benzenesulfonamide hydrochloride

100 mg (0.24 mmol) of N-[6-(4-allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride from Example 13.4 were dissolved in 10 ml of ethyl acetate, after which 10 mg of palladium on active charcoal (10%) were added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After that, the catalyst was filtered off and the filtrate was evaporated down to dryness. After 1 ml of dichloromethane had been added to the resulting residue, diethyl ether was slowly added dropwise until the solution became cloudy. The reaction mixture was stirred for 30 minutes and the precipitate which had formed was filtered off with suction. The filtrate was evaporated down to dryness, after which the residue was dissolved in a 1:1 mixture of dichloromethane and diethyl ether and converted into the hydrochloride by adding ethereal hydrochloric acid. 71 mg (63% of theory) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.9 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (d, 1H); 6.9 (d, 1H); 4.2 (m, 2H); 3.6 (m, 1H); 3.4-3.0 (m, 7H); 1.7 (m, 2H); 1.4 (d, 3H); 1.2 (d, 6H); 0.9 (m, 3H).

MS [m+1]: 417 (free base).

Example 14a 4-Isopropyl-N-{6-[(3S)-methyl-4-propylpiperazin-1-yl]pyridin-3-yl}benzenesulfonamide as free base (S enantiomer)

The preparation was effected in analogy with the preparation of the racemic compound, with enantiomerically pure (2S)-methylpiperazine being used instead of racemic 2-methylpiperazine.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 9.7 (s, 1H); 7.7 (s, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.2 (d, 1H); 6.7 (d, 1H); 3.8 (m, 2H); 2.9 (m, 2H); 2.8 (m, 1H); 2.6 (m, 2H); 2.3 (m, 1H), 2.1 (m, 2H); 1.4 (m, 2H); 1.2 (d, 6H); 1.0 (m, 3H); 0.8 (m, 3H).

MS [m+1-1]: 417 (free base)

Example 15 N-[5-(4-Allylpiperazin-1-yl)pyridin-2-yl]-4-isopropylbenzenesulfonamide hydrochloride 15.1 1-Allyl-4-(6-nitropyridin-3-yl)piperazine

315 mg (2.5 mmol) of N-allylpiperazine were dissolved in 5 ml of toluene under an argon atmosphere. 93 mg (0.1 mmol) of tris-(dibenzylideneacetone)-dipalladium(0) (Pd₂ dba₃), 126 mg (0.2 mmol) of 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (BINAP), 1.14 g (3.5 mmol) of cesium carbonate and 515 mg (2.54 mmol) of 5-bromo-2-nitropyridine were then added and the mixture was stirred at 120° C., in a microwave oven, for 4 hours. After the reaction mixture had cooled down to room temperature, a saturated aqueous solution of ammonium chloride was added. After that, the aqueous reaction mixture was extracted three times with in each case 50 ml of ethyl acetate. After the organic phase had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the residue was chromatographed through silica gel using ethyl acetate/methanol (4:1), with 304 mg (46% of theory) of the title compound being obtained.

¹H-NMR (400 MHz, CDCl₃): δ [ppm] 8.2 (m, 2H); 7.2 (dd, 1H); 5.9 (m, 1H); 5.3 (m, 2H); 3.5 (m, 4H); 3.1 (m, 2H); 2.6 (m, 4H).

MS [m+1]: 249

15.2 5-(4-Allylpiperazin-1-yl)pyridine-2-amine

300 mg (1.21 mmol) of 1-allyl-4-(6-nitropyridin-3-yl)piperazine from Example 15.1 were dissolved in 20 ml of methanol, after which 2.18 g (9.67 mmol) of tin(II) chloride dihydrate were added and the mixture was stirred at 70° C. for 2 hours. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and this mixture was made alkaline using a dilute aqueous solution of sodium hydroxide and extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction. The phases were then separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness, with 183 mg (69% of theory) of the title compound being obtained.

MS [m+1]: 219.

15.3 N-[5-(4-Allylpiperazin-1-yl)pyridin-2-yl]-4-isopropylbenzenesulfonamide hydrochloride

520 mg (2.38 mmol) of 5-(4-allylpiperazin-1-yl)pyridin-2-ylamine and 495 mg (2.26 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 5 ml of tetrahydrofuran at room temperature, after which 1.0 ml (7.15 mmol) of triethylamine was added dropwise and the mixture was stirred at 40-50° C. for 6 hours. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and this mixture was made acid using 1N aqueous hydrochloric acid and extracted twice with diethyl ether. The aqueous phase was made alkaline, to pH 9-10, using a 1N aqueous solution of sodium hydroxide and then extracted twice with ethyl acetate. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the resulting residue was chromatographed on silica gel using ethyl acetate. After the solvent had been removed, the resulting residue was brought into solution using a little diethyl ether in dichloromethane and then converted into the hydrochloride using ethereal hydrochloric acid. 415 mg (44% of theory) of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.6 (bs, 1H); 7.9 (d, 1H); 7.8 (d, 2H); 7.5 (dd, 1H); 7.4 (d, 2H); 7.1 (d, 1H); 6.0 (m, 1H); 5.5 (m, 2H); 3.7 (m, 4H); 3.4 (m, 2H); 3.1 (m, 4H); 3.0 (m, 1H); 1.2 (d, 6H).

¹³C-NMR (100 MHz, DMSO-d₆): δ [ppm] 153.3 (C); 144.5 (C); 141.6 (C); 138.4 (C); 134.3 (CH); 127.3 (CH); 127.0 (CH); 126.8 (CH); 124.8 (CH₂); 113.8 (CH); 57.3 (CH₂); 49.6 (CH₂); 45.2 (CH₂); 33.3 (CH); 23.4 (CH₃).

MS [m+1]: 401.

Example 16 N-[2-(4-Allylpiperazin-1-yl)pyrimidin-5-yl]-4-isopropylbenzenesulfonamide 16.1 2-(4-Allylpiperazin-1-yl)-5-nitropyrimidine

114 mg (2.38 mmol) of 50% sodium hydride were added, under a nitrogen atmosphere and while cooling with ice, to a solution of 273 mg (2.17 mmol) of N-allylpiperazine in 5 ml of dimethylformamide. After 30 minutes, a solution of 440 mg (2.17 mmol) of 2-(methylsulfone)-5-nitropyrimidine in 5 ml of dimethylformamide was added dropwise to the reaction mixture. After 10 minutes, 70 ml of water were added and the reaction mixture was extracted twice with in each case 50 ml of ethyl acetate. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated to dryness, 535 mg (99% of theory) of the title compound were obtained.

¹H-NMR (400 MHz, CDCl₃): δ [ppm] 9.0 (s, 2H); 5.8 (m, 1H); 5.2 (m, 2H); 4.0 (m, 4H); 3.1 (m, 2H); 2.5 (m, 4H).

MS [m+1]: 250.

16.2 2-(4-Allylpiperazin-1-yl)pyrimidine-5-amine

3.84 g (17.0 mmol) of tin(II) chloride dihydrate were added to a solution of 530 mg (2.13 mmol) of 2-(4-allylpiperazin-1-yl)-5-nitropyrimidine from Example 16.1 in 20 ml of methanol and, after that, the reaction mixture was heated at reflux for 1 hour. After the solvent had been evaporated to dryness, the residue was treated with saturated aqueous sodium chloride solution and then made alkaline using dilute aqueous sodium hydroxide solution. After that, the aqueous reaction mixture was extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction. The phases were then separated and the aqueous phase was extracted in each case twice with ethyl acetate and dichloromethane. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, 220 mg (46% of theory) of the title compound were obtained.

16.3 N-[2-(4-Allylpiperazin-1-yl)pyrimidin-5-yl]-4-isopropylbenzenesulfonamide

216 mg (0.98 mmol) of 2-(4-Allylpiperazin-1-yl)pyrimidin-5-ylamine from Example 16.2 and 215 mg (0.98 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, after which 0.4 ml (3.0 mmol) of triethylamine was added dropwise and the mixture was stirred at room temperature overnight. After the solvent had been evaporated down to dryness, water was added to the resulting residue. The aqueous reaction mixture was made acid using 1N aqueous hydrochloric acid and extracted twice with diethyl ether. The aqueous phase was made alkaline to pH 9-10, using a 1N solution of sodium hydroxide and then extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate. The residue which was obtained after filtering off the drying agent and evaporating the solvent down to dryness was thoroughly stirred with a mixture composed of heptane and diethyl ether, filtered off with suction and dried, with 71 mg (18% of theory) of the title compound being obtained.

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.0 (s, 2H); 7.7 (d, 2H); 7.3 (d, 2H); 6.2 (bs, 1H); 5.9 (m, 1H); 5.2 (m, 2H); 3.8 (m, 4H); 3.1 (m, 2H); 3.0 (m, 1H); 2.5 (m, 4H); 1.3 (d, 6H).

MS [m+1]: 402.

Example 17 4-Isopropyl-N-[2-(4-propylpiperazin-1-yl)pyrimidin-5-yl]benzenesulfonamide hydrochloride

70 mg (0.17 mmol) of N-[2-(4-allylpiperazin-1-yl)pyrimidin-5-yl]-4-isopropylbenzenesulfonamide from Example 16.3 were dissolved in 30 ml of ethyl acetate, after which 10 mg of palladium on active charcoal (10%) were added and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was then filtered off and the filtrate was concentrated by evaporation. The residue was brought into solution using 25 ml of diethyl ether and converted into the hydrochloride with ethereal hydrochloric acid, resulting in 58 mg (76% of theory) of the title compound being obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.0 (bs, 1H); 10.0 (s, 1H); 8.1 (s, 2H); 7.7 (d, 2H); 7.5 (d, 2H); 4.6 (m, 2H); 3.5 (m, 2H); 3.4 (m, 2H); 3.0 (m, 5H); 1.7 (m, 2H); 1.3 (d, 6H); 0.9 m, 3H).

MS [m+1]: 404 (free base).

Example 18 N-[6-(4-Allylpiperazin-1-yl)pyrimidin-4-yl]-4-isopropylbenzenesulfonamide 18.1 N-(6-Chloropyrimidin-4-yl)-4-isopropylbenzenesulfonamide

996 mg (5.0 mmol) of isopropylbenzenesulfonamide were dissolved in 20 ml of dimethyl sulfoxide, after which 288 mg (6.0 mmol) of 50% sodium hydride were added and the mixture was stirred at room temperature for 30 minutes. 819 mg (5.5 mmol) of 4,6-dichloropyrimidine were then added and the reaction mixture was stirred overnight at room temperature. Subsequently, the mixture was heated at 90° C. for 3 hours and, after that, stirred at 120° C., in a microwave oven, for 30 minutes. After the reaction mixture had cooled down to room temperature, it was diluted with 150 ml of water, neutralized with citric acid and extracted three times with diethyl ether. The residue, which was obtained after drying with sodium sulfate and after removing the solvent, was dissolved in 100 ml of diethyl ether and extracted with an aqueous solution of sodium hydrogen carbonate. The aqueous phase was acidified and extracted with diethyl ether. The organic phase was dried, filtered and evaporated down to dryness, with 440 mg (28% of theory) of the title compound being obtained.

MS [m+1]: 312.

18.2 N-[6-(4-Allylpiperazin-1-yl)pyrimidin-4-yl]-4-isopropylbenzenesulfonamide

430 mg (1.38 mmol) of N-(6-chloropyrimidin-4-yl)-4-isopropylbenzenesulfonamide from Example 18.1 were dissolved in 3 ml of dimethyl sulfoxide, after which 1.74 g (13.79 mmol) of N-allylpiperazine were added and the mixture was stirred overnight. Subsequently, the reaction mixture was stirred at 100° C., in a microwave oven, for 45 minutes. After the reaction mixture had cooled down to room temperature, it was diluted with 50 ml of water. After that, the aqueous reaction mixture was extracted with 50 ml of ethyl acetate and the precipitate was filtered off with suction, with 190 mg (34% of theory) of the title compound being obtained.

¹H-NMR (400 MHz, CDCl₃): δ [ppm] 8.4 (s, 1H); 7.8 (d, 2H); 7.3 (d, 2H); 6.1 (s, 1H); 5.9 (m, 1H); 5.2 (m, 2H); 3.6 (m, 4H); 3.0 (m, 3H); 2.5 (m, 4H); 1.3 (d, 6H).

MS [m+1]: 402.

Example 19 N-[2-(4-Allylpiperazin-1-yl)pyridin-5-yl]-4-bromobenzenesulfonamide hydrochloride

The preparation was effected in analogy with Example 1.3, with 4-bromobenzenesulfonyl chloride being used instead of 4-isopropylbenzenesulfonyl chloride. The reaction product which was obtained was converted into the hydrochloride using ethereal hydrochloric acid, resulting in 398 mg of the title compound.

MS [m+1]: 436/438

Example 20 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-cyclopropylbenzenesulfonamide

398 mg (0.84 mmol) of N-[6-(4-allylpiperazin-1-yl)pyridin-3-yl]-4-bromobenzenesulfonamide from Example 19, 101 mg (1.18 mmol) of cylcopropylboronic acid, 676 mg (3.19 mmol) of K₃PO₄ and 26 mg (0.09 mmol) of tricyclohexylphosphine were dissolved in 4 ml of toluene and 0.2 ml of water under a nitrogen atmosphere. 10 mg (0.04 mmol) of palladium(II) acetate were then added and the mixture was stirred at 100° C., in a microwave oven, for one hour. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and the mixture was then extracted with ethyl acetate. Because the phases only separated poorly, the finely divided solid was filtered off. The aqueous phase was extracted twice with ethyl acetate. After the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was purified by column chromatography.

MS [m+1]: 399

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.1 (bs, 1H); 9.9 (s, 1H); 7.8 (s, 1H); 7.6 (d, 2H); 7.3 (dd, 1H); 7.2 (d, 2H); 6.9 (d, 1H); 6.0 (m, 1H); 5.5 (d, 2H); 4.3 (m, 2H); 3.8 (m, 2H); 3.4 (m, 2H); 3.2 (m, 2H); 3.0 (m, 2H); 2.0 (m, 1H); 1.0 (m, 2H); 0.8 (m, 2H).

The compounds of the following examples 21 to 40 were prepared in analogous manner:

Example 21 4-Isopropyl-N-[2-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide hydrochloride

MS [m+1]: 403 (free base).

Example 22 4-Isopropyl-N-[2-(3,5-dimethyl-4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide trifluoroacetate

MS [m+1]: 431 (free base).

Example 23 N-[2-(4-Allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide hydrochloride

MS [m+1]: 441 (free base).

Example 24 N-[6-(4-Allyl-3,5-dimethylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride

MS [m+1]: 429 (free base)

Example 25 N-[6-(4-Allyl-3,5-dimethylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide hydrochloride

MS [m+1]: 455 (free base)

Example 26 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide

MS [m+1]: 427

Example 27 4-Bromo-N-[6-(4-propylpiperazin-1yl)pyridin-3-yl]-benzenesulfonamide

MS [m+1]: 439/441

Example 28 4-Chloro-N-[6-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide

MS [m+1]: 395

Example 29 4-Isopropyl-N-[6-(5-propyl-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl]-benzenesulfonamide hydrochloride

MS [m+1]: 415 (free base)

Example 30 N-[6-(5-Allyl-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride

MS [m+1]: 413 (free base)

Example 31 N-[6-(4-Propylpiperazin-1-yl)pyridin-3-yl]-4-vinylbenzenesulfonamide hydrochloride

MS [m+1]: 387 (free base)

Example 32 N-{6-[4-(3-Fluoropropyl)piperazin-1-yl]pyridin-3-yl}-4-isopropylbenzene-sulfonamide hydrochloride

MS [m+1]: 421 (free base)

Example 33 4-Isopropyl-N-[6-(4-prop-2-yn-1-ylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide hydrochloride

MS [m+1-1]: 399 (free base)

Example 34 4-Ethyl-N-[6-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide hydrochloride

MS [m+1]: 389 (free base)

Example 35 N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-chlorobenzenesulfonamide hydrochloride

MS [m+1]: 393 (free base)

Example 36 4-Isopropyl-N-(4-methyl-6-piperazin-1-ylpyridin-3-yl)-benzenesulfonamide hydrochloride

MS [m+1]: 375 (free base)

Example 37 N-[6-(4-Allylpiperazin-1-yl)-4-methylpyridin-3-yl]-4-isopropylbenzene-sulfonamide hydrochloride

MS [m+1]: 415 (free base)

Example 38 4-Isopropyl-N-[4-methyl-6-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide hydrochloride

MS [m+1]: 417 (free base)

Example 39 N-[4-Methyl-6-(4-propylpiperazin-1-yl)pyridin-3-yl]-4-vinylbenzenesulfonamide hydrochloride

MS [m+1]: 401 (free base)

Example 40 N-[6-(4-Butylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide hydrochloride

MS [m+1]: 417 (free base)

Example 41 N-{6-[(3S)-4-Ethyl-3-methylpiperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide hydrochloride

MS [m+1]: 403 (free base)

Example 42 N-[2-(4-Allylpiperazin-1-yl)pyridin-5-yl]-4-(N-pyrrolidinyl)benzene-sulfonamide fumarate

Reaction of 0.300 g of 6-(4-allylpiperazin-1-yl)-2-methylpyridin-3-amine (1.29 mmol) and 0.282 g of 4-isopropylbenzene-1-sulfonyl chloride (1.29 mmol) in 10 ml of a mixture of pyridine and dichloromethane (1:2) yielded 0.465 g (87%) of the title compound as a white solid. The title compound was onverted into the fumarate salt in methanol by addition of fumaric acid.

MS [m+1]: 415

¹H-NMR (400 MHz, CH₃OD): δ [ppm]: 7.6 (d, 2H), 7.5 (d, 2H), 7.3 (m, 1H), 7.2 (m, 1H), 7.1 (d, 1H), 6.5 (d, 1H), 5.9 (m, 1H), 5.4 (m, 2H), 3.5 (m, 5H), 3.0 (m, 4H), 2.8 (m, 2H), 1.9 (s, 3H), 1.2 (m, 6H).

Example 43 4-Isopropyl-[N-[2-(4-allylpiperazin-1-yl)-6-methylpyridin-5-yl]-4-(N-pyrrolidinyl)benzenesulfonamide, Fumarate

Reaction of 0.300 g of 6-(4-allylpiperazin-1-yl)-2-methylpyridin-3-amine (1.29 mmol) and 0.282 g of 4-isopropylbenzene-1-sulfonyl chloride (1.29 mmol) in 10 ml of a mixture of pyridine/dichloromethane (1:2) yielded 0.465 g (87%) of the title compound as a white solid. The title compound was onverted into the fumarate salt in methanol by addition of fumaric acid.

MS [m+1]: 415

¹H-NMR (400 MHz, MeOD): δ [ppm] 7.6 (d, 2H), 7.5 (d, 2H), 7.3 (m, 1H), 7.2 (m, 1H), 7.1 (d, 1H), 6.5 (d, 1H), 5.9 (m, 1H), 5.4 (m, 2H), 3.5 (m, 5H), 3.0 (m, 4H), 2.8 (m, 2H), 1.9 (s, 3H), 1.2 (m, 6H).

Example 44 4-tert-Butyl-N-[2-(4-allylpiperazin-1-yl)-6-methylpyridin-5-yl]-benzenesulfonamide, fumarate

Reaction of 0.300 g of 6-(4-allylpiperazin-1-yl)-2-methylpyridin-3-amine (1.29 mmol) and 0.300 g of 4-tert-butylbenzene-1-sulfonyl chloride (1.29 mmol) in 10 ml of a mixture of pyridine/dichloromethane (1:2) yielded 0.525 g (95%) of the title compound as a white solid. The title compound was onverted into the fumarate salt in methanol by addition of fumaric acid.

MS [m+1]: 429

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 9.3 (s, 2H), 8.6 (d, 2H), 7.8 (m, 1H), 7.4 (m, 2H), 7.0 (d, 1H), 6.6 (d, 1H), 5.8 (m, 1H), 5.2 (m, 2H), 3.4 (m, 4H), 2.9 (m, 2H), 2.4 (m, 4H), 1.9 (s, 3H), 1.3 (s, 9H).

Example 45 4-tert-pentyl-[N-[2-(4-Allylpiperazin-1-yl)-6-methylpyridin-5-yl]-benzenesulfonamide, Fumarate

Reaction of 0.300 g of 6-(4-allylpiperazin-1-yl)-2-methylpyridin-3-amine (1.29 mmol) and 0.318 g of 4-tert-pentylbenzene-1-sulfonyl chloride (1.29 mmol) in 10 mL pyridine-dichloromethane (1:2) yielded 0.564 g (99%) of the title compound as a white solid. The title compound was onverted into the fumarate salt in methanol by addition of fumaric acid.

MS [m+1]: 443

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 9.3 (s, 2H), 8.6 (d, 2H), 7.8 (m, 1H), 7.4 (m, 2H), 7.0 (d, 1H), 6.5 (d, 1H), 5.8 (m, 1H), 5.2 (m, 2H), 3.4 (m, 4H), 3.0 (m, 2H), 2.4 (m, 4H), 1.9 (s, 3H), 1.6 (m, 2H), 1.2 (s, 6H), 0.6 (t, 3H).

The compounds of Examples 46 to were prepared in analogous manner:

Example 46 4-Ethyl-N-[6-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-benzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.9 (bs, 1H); 10.0 (s, 1H); 7.8 (m, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (dd, 1H); 6.9 (d, 1H); 4.3 (m, 2H); 3.5-2.9 (m, 7H); 2.7 (m, 2H); 1.7 (m, 2H); 1.4 (m, 2H); 1.2 (m, 4H); 0.9 (t, 3H).

MS [m+1]: 403

Example 47 N-[6-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-4-vinylbenzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.4 (bs, 1H); 10.0 (s, 1H); 7.8 (s, 1H); 7.7 (m, 4H); 7.3 (d, 1H); 6.9 (d, 1H); 6.8 (dd, 1H); 6.0 (d, 1H); 5.4 (d, 1H); 4.3 (m, 2H); 3.5 (m, 1H); 3.3-2.9 (m, 6H); 1.7 (m, 2H); 1.4 (m, 2H); 1.2 (m, 1H); 0.9 (t, 3H).

MS [m+1]: 401

Example 48 N-[6-((S)-4-Allyl-3-methyl-piperazin-1-yl)-2-methoxy-pyridin-3-yl]-4-isopropyl-benzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.1 (bs, 1H); 9.2 (s, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (m, 1H); 6.4 (m, 1H); 6.0 (m, 1H); 5.5 (m, 2H); 4.3 (m, 2H); 4.0 (m, 1H); 3.7 (m, 2H); 3.4-3.2 (m, 5H); 3.1 (m, 1H); 3.0 (m, 2H); 1.4 (m, 2H); 1.2 (m, 7H).

MS [m+1]: 445

Example 49 4-Isopropyl-N-[2-methoxy-6-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-benzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.8 (bs, 1H); 9.3 (s, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (m, 1H); 6.4 (m, 1H); 4.2 (m, 2H); 3.5-3.2 (m, 8H); 3.1 (m, 1H); 3.0 (m, 2H); 1.7 (m, 2H); 1.4 (m, 2H); 1.2 (m, 7H); 0.9 (t, 3H).

MS [m+1]: 447

Example 50 N-[6-((S)-4-Allyl-3-ethyl-piperazin-1-yl)-pyridin-3-yl]-4-isopropylbenzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.2 (bs, 1H); 10.0 (s, 1H); 7.8 (d, 1H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (m, 1H); 6.9 (d, 1H); 6.0 (m, 1H); 5.5 (m 2H); 4.2 (m, 2H); 4.0 (m, 2H); 3.4-3.0 (m, 6H); 1.7 (m, 2H); 1.2 (d, 6H); 1.0 (t, 3H).

MS [m+1]: 429

Example 51 N-[6-((S)-3-Ethyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-4-isopropylbenzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.2 (bs, 1H); 10.2 (s, 1H); 7.8 (d, 1H); 7.7 (d, 2H); 7.4 (m, 3H); 7.0 (d, 1H); 4.2 (m, 2H); 3.6-3.0 (m, 8H); 2.0 (m, 1H); 1.7 (m, 3H); 1.2 (d, 6H); 1.0 (m, 6H).

MS [m+1]: 431

Example 52 4-Isopropyl-N-(2-piperazin-1-yl-pyrimidin-5-yl)-benzenesulfonamide

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 8.0 (s, 2H); 7.6 (d, 2H); 7.4 (d, 2H); 3.6 (m, 4H); 3.0 (m, 1H); 2.7 (m, 4H); 1.2 (d, 6H).

MS [m+1]: 362

Example 53 N-[2-(4-Ethyl-piperazin-1-yl)-pyrimidin-5-yl]-4-isopropyl-benzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, D₂O): δ [ppm] 7.7 (s, 2H); 7.3 (d, 2H); 7.1 (d, 2H); 4.3 (m, 2H); 3.3 (m, 2H); 3.0 (m, 4H); 2.7 (m, 3H); 1.0 (t, 3H); 0.9 (d, 6H).

MS [m+1]: 390

Example 54 N-[2-((S)-4-Ethyl-3-methyl-piperazin-1-yl)-pyrimidin-5-yl]-4-isopropylbenzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.7 (bs, 1H); 10.0 (s, 1H); 8.1 (m, 2H); 7.6 (d, 2H); 7.4 (d, 2H); 4.6 (m, 2H); 3.4 (m, 4H); 3.2 (m, 1H); 3.0 (m, 3H); 1.4 (m, 2H); 1.2 (m, 10H).

MS [m+1]: 404

Example 55 N-[2-((S)-4-Allyl-3-methyl-piperazin-1-yl)-pyrimidin-5-yl]-4-isopropylbenzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.0 (bs, 1H); 10.0 (s, 1H); 8.1 (s, 2H); 7.6 (d, 2H); 7.4 (d, 2H); 6.0 (m, 1H); 5.5 (m, 2H); 4.6 (m, 2H); 4.0 (m, 2H); 3.7 (m, 2H); 3.3 (m, 3H); 3.0 (m, 1H); 1.4 (m, 2H); 1.2 (m, 7H).

MS [m+1]: 416

Example 56 4-Isopropyl-N-[2-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyrimidin-5-yl]-benzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.6 (bs, 1H); 10.0 (s, 1H); 8.1 (m, 2H); 7.6 (d, 2H); 7.4 (d, 2H); 4.5 (m, 2H); 3.5 (m, 2H); 3.3 (m, 3H); 3.0 (m, 3H); 1.7 (m, 2H); 1.4 (m, 2H); 1.2 (m, 7H); 0.9 (t, 3H).

MS [m+1]: 418

Example 57 4-Ethyl-N-[2-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyrimidin-5-yl]-benzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.8 (bs, 1H); 10.0 (s, 1H); 8.1 (m, 2H); 7.6 (d, 2H); 7.4 (d, 2H); 4.5 (m, 2H); 3.5 (m, 2H); 3.3 (m, 3H); 3.0 (m, 2H); 2.7 (m, 2H); 1.7 (m, 2H); 1.4 (m, 2H); 1.2 (m, 4H); 0.9 (t, 3H).

MS [m+1]: 404

Example 58 N-[2-((S)-3-Methyl-4-propyl-piperazin-1-yl)-pyrimidin-5-yl]-4-vinylbenzenesulfonamide, hydrochloride

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 10.7 (bs, 1H); 10.0 (s, 1H); 8.1 (d, 2H); 7.7 (m, 4H); 6.8 (dd, 1H); 6.0 (d, 1H); 5.5 (d, 1H); 4.5 (m, 2H); 3.5 (m, 2H); 3.3 (m, 3H); 3.0 (m, 2H); 1.7 (m, 2H); 1.4 (m, 2H); 1.2 (m, 1H); 0.9 (t, 3H).

MS [m+1]: 402

Example 59 4-Isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester

59.1 4-Isopropyl-benzenesulfonic acid 6-chloro-pyridin-3-yl ester

A reaction flask containing 500 mg of 6-chloropyridin-3-ol (3.86 mmol) and 844 mg of 4-isopropyl-benzenesulfonylchloride (0.20 mmol) in dry tetrahydrofurane (10 ml) was flushed with N₂. 1.6 ml of triethylamine were added and the reaction mixture was stirred at room temperature for 2 h. Thereby 4-isopropyl-benzenesulfonic acid 6-chloropyridin-3-yl ester ester was obtained in 98% yield.

MS [m+1]: 312

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 8.1 (d, 1H); 7.8 (d, 2H); 7.6 (m, 4H); 3.0 (m, 1H); 1.2 (d, 6H).

59.2 4-Isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester

A flask containing 45 mg of palladium(II) acetate (0.2 mmol), 126 mg of BINAP (0.20 mmol) and 0.233 mg of sodium tert-butylate in dry toluene (15 mL) was flushed with nitrogen 1.275 g of 1-allylpiperazin (10 mmol) were added and the reaction mixture was heated to 50° C. 630 mg of 4-isopropyl-benzenesulfonic acid 6-chloro-pyridin-3-yl ester (2.0 mmol) were dissolved in toluene and the solution was slowly added over a period of 10 minutes into the reaction mixture with stirring. The mixture was heated to reflux with stirring for 7 h. Thereby 4-isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester was obtained in 21% yield.

MS [m+1]: 402

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 7.8 (d, 2H); 7.7 (d, 1H); 7.6 (d, 2H); 7.2 (dd, 1H); 6.8 (d, 1H); 5.8 (m, 1H); 5.2 (m, 2H); 3.5 (m, 4H); 3.0 (m, 3H); 2.5 (m, 4H); 1.2 (d, 6H).

Example 60 4-Isopropyl-benzenesulfonic acid 6-(4-propyl-piperazin-1-yl)-pyridin-3-yl ester, hydrochloride

In a reaction flask 5 mg of palladium on charcoal were added to 50 mg of 4-isopropylbenzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester from example 59(0.12 mmol) in dry ethyl acetate (5 ml). The atmosphere was then charged with hydrogen gas and the reaction mixture was stirred at room temperature for 1 hour. Thereby, 4-isopropyl-benzenesulfonic acid 6-(4-propyl-piperazin-1-yl)-pyridin-3-yl ester were obtained in 58% yield. The compound was converted into its hydrochloride salt by addition of HCl in ether.

MS [m+1]: 404

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] 11.0 (bs, 1H); 7.8 (m, 3H); 7.6 (d, 2H); 7.3 (dd, 1H); 6.9 (d, 1H); 4.3 (d, 2H); 3.5 (d, 2H); 3.3 (dd, 2H); 3.0 (m, 5H); 1.7 (m, 2H); 1.3 (d, 6H); 0.9 (t, 3H).

Examples of galenic administration forms

A) Tablets

Tablets of the following composition are pressed on a tablet press in the customary manner:

-   -   40 mg of substance from Example 2     -   120 mg of corn starch     -   13.5 mg of gelatin     -   45 mg of lactose     -   2.25 mg of Aerosil® (chemically pure silicic acid in         submicroscopically fine dispersion)     -   6.75 mg of potato starch (as a 6% paste)         B) Sugar-Coated Tablets     -   20 mg of substance from Example 2     -   60 mg of core composition     -   70 mg of saccharification composition     -   The core composition consists of 9 parts of corn starch, 3 parts         of lactose and 1 part of 60:40 vinylpyrrolidone/vinyl acetate         copolymer. The saccharification composition consists of 5 parts         of cane sugar, 2 parts of corn starch, 2 parts of calcium         carbonate and 1 part of talc. The sugar-coated tablets which had         been prepared in this way are subsequently provided with a         gastric juice-resistant coating.         Biological Investigations—Receptor Binding Studies:

The substance to be tested was either dissolved in methanol/Chremophor® (BASF-AG) or in dimethyl sulfoxide and then diluted with water to the desired concentration.

Dopamine D₃ receptor:

The assay mixture (0.250 ml) was composed of membranes derived from ˜10⁶ HEK-293 cells possessing stably expressed human dopamine D₃ receptors, 0.1 nM [¹²⁵I]-iodosulpride and incubation buffer (total binding) or, in addition, test substance (inhibition curve) or 1 μM spiperone (nonspecific binding). Each assay mixture was run in triplicate.

The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin, 10 μM quinolone and 0.1% ascorbic acid (prepared fresh daily). The buffer was adjusted to pH 7.4 with HCl.

Dopamine D_(2L) Receptor:

The assay mixture (1 ml) was composed of membranes from ˜10⁶ HEK-293 cells possessing stably expressed human dopamine D_(2L) receptors (long isoform) and 0.01 nM [¹²⁵I] iodospiperone and incubation buffer (total binding) or, in addition, test substance (inhibition curve) or 1 μM haloperidol (nonspecific binding). Each assay mixture was run in triplicate.

The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin. The buffer was adjusted to pH 7.4 with HCl.

Measurement and Analysis:

After having been incubated at 25° C. for 60 minutes, the assay mixtures were filtered through a Whatman GF/B glass fiber filter under vacuum using a cell collecting device. The filters were transferred to scintillation viols using a filter transfer system. After 4 ml of Ultima Gold® (Packard) have been added, the samples were shaken for one hour and the radioactivity was then counted in a Beta-Counter (Packard, Tricarb 2000 or 2200CA). The cpm values were converted into dpm using a standard quench series and the program belonging to the instrument.

The inhibition curves were analyzed by means of iterative nonlinear regression analysis using the Statistical Analysis System (SAS) which is similar to the “LIGAND” program described by Munson and Rodbard.

In these tests, the compounds according to the invention exhibit very good affinities for the D₃ receptor (<100 nM, frequently <50 nM) and bind selectively to the D₃ receptor. The results of the binding tests are given in Table 1.

TABLE 1 K_(i) (D₃) Selectivity Example [nM] vs. D₂L*  1  3.0 232  2  5.5  25  3  5.9  15  5 11.4 108  6  9.7 169  7 11.4  68 10  7.5  93 11  6.2  77 13  3.6 131 13a  2.7  96 14  2.5  81 14a  1.5 184 16  3.8 131 17  8.2 148 19 36.9  91 22 21.9  22 24 25.0  47 27 21.4  55 28 25.3  67 29 16.9  31 30 11.1  17 31 14.0  96 32 17.0  74 34  9.6  73 35 26.6  51 36  5.4  50 37  2.7  86 38 17.2  22 39 34.6  30 42  5.3  33 43  1.1  80 44  1.4  41 45  1.4  24 46  7.1  50 47  6.1 118 48  0.8  21 49  0.4  19 50  9.9  57 51  3.1 101 52 14.2  63 53  8.8 149 54  2.3  84 55  2.9 159 56  1.6 399 57  7.3 234 58  6.2 254 59 16.2  75 60 17.4  47 *K_(i)(D₃)/K_(i)(D_(2L)) 

The invention claimed is:
 1. A compound selected from the group consisting of: N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-propylbenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-butylbenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-ethylbenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-vinylbenzenesulfonamide; 4-Isopropyl-N-(6-piperazin-1-ylpyridin-3-yl)benzenesulfonamide; N-{6-[4-(Cyclohexylmethyl)piperazin-1-yl]pyridin-3-yl}-4-isopropyl-benzenesulfonamide; N-[6-(4-Isobutylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; 4-Isopropyl-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]benzenesulfonamide; N-[6-(4-Ethylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-{6-[4-(Cyclopropylmethyl)piperazin-1-yl]pyridin-3-yl}-4-isopropyl-benzenesulfonamide; N-[6-(4-Allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-{6-[4-Allyl-(3S)-methylpiperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide, S enantiomer; 4-Isopropyl-N-[6-(3-methyl-4-propylpiperazin-1-yl)pyridin-3-yl]benzenesulfonamide; 4-Isopropyl-N-{6-[(3S)-methyl-4-propylpiperazin-1-yl]pyridin-3-yl}benzenesulfonamide, S enantiomer; N-[5-(4-Allylpiperazin-1-yl)pyridin-2-yl]-4-isopropylbenzenesulfonamide; N-[2-(4-Allylpiperazin-1-yl)pyrimidin-5-yl]-4-isopropylbenzenesulfonamide; 4-Isopropyl-N-[2-(4-propylpiperazin-1-yl)pyrimidin-5-yl]benzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyrimidin-4-yl]-4-isopropylbenzenesulfonamide; N-[2-(4-Allylpiperazin-1-yl)pyridin-5-yl]-4-bromobenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-cyclopropylbenzenesulfonamide; 4-Isopropyl-N-[2-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide; 4-Isopropyl-N-[2-(3,5-dimethyl-4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide; N-[2-(4-Allyl-3-methylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide; N-[6-(4-Allyl-3,5-dimethylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-[6-(4-Allyl-3,5-dimethylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide; 4-Bromo-N-[6-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide; 4-Chloro-N-[6-(4-propylpiperazin-1 yl)pyridin-3-yl]-benzenesulfonamide; 4-Isopropyl-N-[6-(5-propyl-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl]-benzenesulfonamide; N-[6-(5-Allyl-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-[6-(4-Propylpiperazin-1-yl)pyridin-3-yl]-4-vinylbenzenesulfonamide; N-{6-[4-(3-Fluoropropyl)piperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide; 4-Isopropyl-N-[6-(4-prop-2-yn-1-ylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide; 4-Ethyl-N-[6-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)pyridin-3-yl]-4-chlorobenzenesulfonamide; 4-Isopropyl-N-(4-methyl-6-piperazin-1-ylpyridin-3-yl)-benzenesulfonamide; N-[6-(4-Allylpiperazin-1-yl)-4-methylpyridin-3-yl]-4-isopropylbenzenesulfonamide; 4-Isopropyl-N-[4-methyl-6-(4-propylpiperazin-1-yl)pyridin-3-yl]-benzenesulfonamide; N-[4-Methyl-6-(4-propylpiperazin-1-yl)pyridin-3-yl]-4-vinylbenzenesulfonamide; N-[6-(4-Butylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-{6-[(3S)-4-Ethyl-3-methylpiperazin-1-yl]pyridin-3-yl}-4-isopropylbenzenesulfonamide; N-[2-(4-Allylpiperazin-1-yl)pyridin-5-yl]-4-(N-pyrrolidinyl)benzenesulfonamide; 4-Isopropyl-[N-[2-(4-allylpiperazin-1-yl)-6-methylpyridin-5-yl]-4-(N-pyrrolidinyl)benzenesulfonamide; 4-tert-Butyl-[N-[2-(4-allylpiperazin-1-yl)-6-methylpyridin-5-yl]-benzenesulfonamide; 4-tert-pentyl-[N-[2-(4-allylpiperazin-1-yl)-6-methylpyridin-5-yl]-benzenesulfonamide; 4-Ethyl-N-[6-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-benzenesulfonamide; N-[6-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-4-vinylbenzenesulfonamide; N-[6-((S)-4-Allyl-3-methyl-piperazin-1-yl)-2-methoxy-pyridin-3-yl]-4-isopropyl-benzenesulfonamide; 4-Isopropyl-N-[2-methoxy-6-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-benzenesulfonamide; N-[6-((S)-4-Allyl-3-ethyl-piperazin-1-yl)-pyridin-3-yl]-4-isopropylbenzenesulfonamide; N-[6-((S)-3-Ethyl-4-propyl-piperazin-1-yl)-pyridin-3-yl]-4-isopropylbenzenesulfonamide; 4-Isopropyl-N-(2-piperazin-1-yl-pyrimidin-5-yl)-benzenesulfonamide; N-[2-(4-Ethyl-piperazin-1-yl)-pyrimidin-5-yl]-4-isopropyl-benzenesulfonamide; N-[2-((S)-4-Ethyl-3-methyl-piperazin-1-yl)-pyrimidin-5-yl]-4-isopropyl-benzenesulfonamide; N-[2-((S)-4-Allyl-3-methyl-piperazin-1-yl)-pyrimidin-5-yl]-4-isopropylbenzenesulfonamide; 4-Isopropyl-N-[2-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyrimidin-5-yl]-benzenesulfonamide; 4-Ethyl-N-[2-((S)-3-methyl-4-propyl-piperazin-1-yl)-pyrimidin-5-yl]-benzenesulfonamide; N-[2-((S)-3-Methyl-4-propyl-piperazin-1-yl)-pyrimidin-5-yl]-4-vinyl-benzenesulfonamide; 4-Isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester; and, 4-Isopropyl-benzenesulfonic acid 6-(4-propyl-piperazin-1-yl)-pyridin-3-yl ester; or a physiologically tolerated acid addition salt thereof, or an N-oxide thereof.
 2. A compound that is N-[6-(4-allylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide, a physiologically tolerated acid addition salt thereof, or an N-oxide thereof.
 3. A pharmaceutical composition comprising a compound as claimed in claim 1, a physiologically tolerated acid addition salt thereof, or an N-oxide thereof, and a physiologically acceptable carrier and/or an auxiliary substance. 